Acetylenes disubstituted with a 5 alkyl, aryl or heteroaryl substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity

ABSTRACT

Compounds of the formula ##STR1## wherein the symbols have the meaning described in the specification, have retinoid-like biological activity.

This application is a divisional of application Ser. No. 08/366,193,filed on Dec. 29, 1994, now U.S. Pat. No. 5,648,514.

FIELD OF THE INVENTION

The present invention relates to novel compounds having retinoid-likeactivity. More specifically, the present invention relates to compoundshaving an acetylene portion which is substituted with a 5 substituteddihydronaphthyl and by a substituted aryl or substituted heteroarylgroup having an acid function. The acid function may also be convertedto an alcohol, aldehyde or ketone or derivatives thereof, or may bereduced to --CH₃.

BACKGROUND ART

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil®, diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

U.S. Pat. No. 4,740,519 (Shroot et al.), U.S. Pat. No. 4,826,969(Maignan et al.), U.S. Pat. No. 4,326,055 (Loeliger et al.), U.S. Pat.No. 5,130,335 (Chandraratna et al.), U.S. Pat. No. 5,037,825 (Klaus etal.), U.S. Pat. No. 5,231,113 (Chandraratna et al.), U.S. Pat. No.5,324,840 (Chandraratna), Published European Patent Application Nos. 0176 034 A (Wuest et al.), 0 350 846 A (Klaus et al.), 0 176 032 A(Frickel et al.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus etal.), 0 303 915 A (Bryce et al.), UK Patent Application GB 2190378 A(Klaus et al.), German Patent Application Nos. DE 3715955 A1 (Klaus etal.), DE 3602473 A1 (Wuest et al., and the articles J. Amer. Acad. Derm.15: 756-764 (1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985)(Shudo et al.), J. Med Chem. 1988 31, 2182-2192 (Kagechika et al.),Chemistry and Biology of Synthetic Retinoids CRC Press Inc. 1990 p334-335, 354 (Dawson et al.), describe or relate to compounds whichinclude a tetrahydronaphthyl moiety and have retinoid-like or relatedbiological activity. U.S. Pat. No. 4,391,731 (Boller et al.) describestetrahydronaphthalene derivatives which are useful in liquid crystalcompositions. Several co-pending applications and recently issuedpatents which are assigned to the assignee of the present application,are directed to further compounds having retinoid-like activity.

SUMMARY OF THE INVENTION

The present invention covers compounds of Formula 7 ##STR2## wherein R₁is hydrogen or alkyl of 1 to 10 carbons; R₂ and R₃ are hydrogen, oralkyl of 1 to 6 carbons and the substituted ethynyl group occupieseither the 2 or the 3 position of the dihydronaphthalene nucleus;

m is an integer having the value of 0-3;

o is an integer having the value 0-3;

Y is a phenyl group, or heteroaryl selected from a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, said groups being optionally substituted withone or two R₂ groups;

A is (CH₂)n where n is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-lower alkylsilyl, where R₇ isan alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ isan alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and

R₂₂ is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 doublebonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl, C₁ -C₁₀-alkylphenyl, naphthyl, C₁ -C₁₀ -alkylnaphthyl, phenyl-C₁ -C₁₀ alkyl,naphthyl-C₁ -C₁₀ alkyl, C₁ -C₁₀ -alkenylphenyl having 1 to 3 doublebonds, C₁ -C₁₀ -alkynylphenyl having 1 to 3 triple bonds, phenyl-C₁ -C₁₀alkenyl having 1 to 3 double bonds, phenyl-C₁ -C₁₀ alkynyl having 1 to 3triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbonsor acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where theacyl group is represented by COR₁₄, CN, CON(R₁)₂, (CH₂)_(p) CO₂ R₈ wherep is an integer between 0 to 10, or R₂₂ is aminoalkyl or thioalkyl of 1to 10 carbons, or a 5 or 6 membered heteroaryl group optionallysubstituted with a C₁ to C₁₀ alkyl group and having 1 to 3 heteroatoms,said heteroatoms being selected from a group consisting of O, S, and N,or R₂₂ is represented by (CH₂)_(p) XR₁ or by (CH₂)_(p) NR₁ R₂ ; where Xis O or S, the R₁₄ group is hydrogen, alkyl of 1 to 10 carbons, alkenylof 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10carbons and 1 to 3 triple bonds, carbocyclic aryl selected from thegroup consisting of phenyl, C₁ -C₁₀ -alkylphenyl, naphthyl, C₁ -C₁₀-alkylnaphthyl, phenyl-C₁ -C₁₀ alkyl, or naphthyl-C₁ -C₁₀ alkyl.

In a second aspect, this invention relates to the use of the compoundsof Formula 7 for the treatment of skin-related diseases, including,without limitation, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 7 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to processes for making acompound of Formula 7 which process comprises reacting a compound ofFormula 8 with a compound of Formula 9, in the presence of cuprousiodide and Pd(PQ₃)₂ Cl₂ (Q is phenyl) or a similar complex, or reactingthe zinc salt of the compound shown in Formula 8 with a compound ofFormula 9 in the presence of Pd(PQ₃)₄ (Q is phenyl) or similar complex.In Formula 8 the symbol SDHN represents a dihydronaphthalene nucleuswhich is appropriately substituted to provide the compounds defined inFormula 7, or said dihydronaphthalene nucleus is appropriatelysubstituted to provide such precursors of compounds of the Formula 7from which the target compounds can be readily obtained by organicreactions well known in the art. In Formula 9 X₁ is halogen, B' is H, ora protected acid, alcohol, aldehyde, or ketone. In effect, B' is eitherthe desired B group of Formula 7, or B' is a precursor from which the Bgroup can be readily obtained by reactions well known in the art.##STR3##

Still further, the present invention relates to such reactions performedon the compounds of Formula 7 which cause transformations of the A-Bgroup or of the substituents on the dihydronaphthalene moiety, while thereaction product still remains within the scope of Formula 7.

General Embodiments

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and as applicable 3to 6 carbons for lower branch chained and cycloalkyl groups. Loweralkenyl is defined similarly having 2 to 6 carbons for normal loweralkenyl groups, and 3 to 6 carbons for branch chained and cyclo-loweralkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6carbons for normal lower alkynyl groups, and 4 to 6 carbons for branchchained lower alkynyl groups.

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. It includes organic and inorganic esters. Where B (of Formula7) is --COOH, this term covers the products derived from treatment ofthis function with alcohols or thiols preferably with aliphatic alcoholshaving 1-6 carbons. Where the ester is derived from compounds where B is--CH₂ OH, this term covers compounds derived from organic acids capableof forming esters including phosphorous based and sulfur based acids, orcompounds of the formula --CH₂ OCOR₁₁ where R₁₁ is any substituted orunsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromaticgroup, preferably with 1-6 carbons in the aliphatic portions.

Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula-CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₇ O-- where R₇ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds inthis invention having a functionality capable of forming a salt, forexample an acid functionality. A pharmaceutically acceptable salt is anysalt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri-acid may also be used.

Some of the compounds of the present invention may have trans and cis (Eand Z) isomers. In addition, the compounds of the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all such isomers per se, as well asmixtures of cis and trans isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well. In the presentapplication when no specific mention is made of the configuration (cis,trans or R or S) of a compound (or of an asymmetric carbon) then amixture of such isomers, or either one of the isomers is intended.

Referring now to the nomenclature used in naming the compounds of theinvention and intermediate compounds leading thereto, two differentsystems for numbering the tetrahydronaphthalene ring are demonstrated asshown by the structural formulas of Compounds F, G and 1. Compound 1 andCompounds F and G are exemplary intermediates utilized in the synthesisof the compounds of the invention. The numbering systems illustratedhere will not only be readily apparent to those skilled in the art, butwill be readily understood as it is applied in the ensuing descriptionof the compounds of the invention and of intermediates utilized forobtaining the compounds of the invention. ##STR4##

With reference to the symbol Y in Formula 7, the preferred compounds ofthe invention are those where Y is phenyl, pyridyl, thienyl or furyl.Even more preferred are compounds where Y is phenyl or pyridyl. As faras substititutions on the Y (phenyl) and Y (pyridyl) groups areconcerned, compounds are preferred where the phenyl group is 1,4 (Para)substituted, and where the pyridine ring is 2,5 substituted.(Substitution in the 2,5 positions in the "pyridine" nomenclaturecorresponds to substitution in the 6-position in the "nicotinic acid"nomenclature.) In the preferred compounds of the invention there is nooptional R₂ substituent on the Y group.

The A-B group of the preferred compounds is (CH₂)_(n) --COOH or(CH₂)_(n) --COOR₈, where R₈ is defined as above. Even more preferably nis zero and R₈ is lower alkyl.

The aromatic portion of the tetrahydronaphthalene or dihydronaphthalenemoiety is preferably substituted only by the acetylene function. Inother words, in the preferred compounds there is no R₂ substituent(other than hydrogen). Similarly, in the preferred compounds of theinvention there is no R₃ substituent (other than hydrogen). The R₁substituent of the compounds of the invention is preferably lower alkyl,and even more preferably methyl.

In the preferred compounds of the invention R₂₂ is preferably hydrogen,alkyl of 1-10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond,alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkylhaving 1 to 10 carbons in the alkyl group, phenylalkynyl having 2 to 10carbons in the alkynyl group, CH₂ CO₂ R₈, hydroxyalkyl having 1 to 10carbons in the alkyl group, hydroxyalkynyl having 2 to 10 carbons in thealkynyl group, cyano (CN), CONH₂ or heteroaryl. Among the heteroarylgroups 5 or 6 membered rings having 1 or 2 heteroatoms are particularlypreferred. Compounds where the R₂₂ group is 2-thiazolyl, 2-furyl,2-thienyl or 2-pyridyl are especially preferred. Specific preferredcompounds of the invention and their synthesis are described below inthe section of this application titled "Specific Examples". Thepresently most preferred compounds of the invention in accordance withFormula 7 are indicated in Table 1 below, with reference to Formula 7A.The numbering system used for the compounds of the invention is inaccordance with the example shown above for Compound 1. ##STR5##

                  TABLE 1                                                         ______________________________________                                                 Position                                                                      of Ethynyl                                                           Compound No.                                                                           Substituent                                                                              R.sub.8                                                                              R.sub.22                                           ______________________________________                                        67       3          Et     2-thiazolyl                                        69       3          Et     4-t-butylphenyl                                    70       3          Et     2-pyridyl                                          71       3          Et     t-butyl                                            72       3          Et     H                                                  73       3          Et     CH.sub.3 --                                        74       3          Et     CH.sub.3 (CH.sub.2).sub.3 -- (n-butyl)             76       3          Et     1-(3,3-dimethyl)butynyl-                           77       3          Et     CH.sub.3 CC-- (1-propynyl)                         78       3          H      2-thiazolyl                                        79       3          H      phenyl                                             80       3          H      t-butyl                                            81       3          H      H                                                  82       3          H      methyl                                             83       3          H      CH.sub.3 (CH.sub.2).sub.3 -- (n-butyl)             84       3          H      CH.sub.3 (CH.sub.2).sub.2 CC-- (1-pentynyl)        85       3          H      1-(3,3-dimethyl)butynyl-                           86       3          H      CH.sub.3 CC-- (1-propynyl)                         88       2          Et     2-thiazolyl                                        89       2          Et     phenyl                                             90       2          Et     phenylethynyl                                      91       2          Et     1-(3-hydroxy-3-methyl)butynyl                      92       2          Et     CH.sub.3 CC-- (1-propynyl)                         93       2          Et     CH.sub.2 (CH.sub.2).sub.2 CC-- (1-pentynyl)        94       2          Et     1-(3,3-dimethyl)butynyl                            95       2          Et     methyl                                             96       2          Et     t-butyl                                            97       2          H      phenyl                                             98       2          H      phenylethyn-1-yl                                   99       2          H      1-(3-hydroxy-3-methyl)butynyl                      100      2          H      CH.sub.3 CC-- (1-propynyl)                         101      2          H      1-(3,3-dimethyl)butynyl                            102      2          H      methyl                                             103      2          H      t-butyl                                            104      2          H      2-thiazolyl                                        108      2          Et     CN                                                 109      2          Et     CONH.sub.2                                         110      2          Et     H                                                  114      2          Et     CH.sub.2 CO.sub.2 Et                               120      3          Et     CH.sub.2 CO.sub.2 Et                               122      3          Et     2-furyl                                            123      3          Et     2-thienyl                                          124      3          H      2-furyl                                            125      3          H      2-thienyl                                          129      3          H      CN                                                 130      2          H      CN                                                 163      3          Et     4-Mephenyl                                         164      3          H      4-Mephenyl                                         ______________________________________                                    

Modes of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards it expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per mililiter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

Assay of Retinoid-like Biological Activity

The retinoic acid-like activity of these compounds is confirmed throughthe classic measure of retinoic acid activity involving the effects ofretinoic acid on ornithine decarboxylase. The original work on thecorrelation retinoic acid and decrease in cell proliferation was done byVerma & Boutwell, Cancer Research, 1977, 2196-2201. That referencediscloses that ornithine decarboxylase (ODC) activity increasedprecedent to polyamine biosynthesis. It has been established elsewherethat increases in polyamine synthesis can be correlated or associatedwith cellular proliferation. Thus, if ODC activity could be inhibited,cell hyperproliferation could be modulated. Although all cases for ODCactivity increases are unknown, it is known that12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Research:1662-1670,1975 may be used to demonstrate inhibition of TPA induction ofODC by compounds of the invention. Activity of exemplary compounds ofthe present invention in the above-described ODC assay is disclosed inTable 2 which provides the IC₈₀ concentration for the respectiveexemplary compound. ("IC₈₀ " is that concentration of the test compoundwhich causes 80% inhibition in the ODC assay. By analogy, "IC₆₀, forexample, is that concentration of the test compound which causes 60%inhibition in the ODC assay.)

                  TABLE 2                                                         ______________________________________                                        Compound #         IC.sub.80 conc (nmols)                                     ______________________________________                                        67                  56.70                                                     71                  3.3                                                       74                  <0.3                                                      76                 100 (IC.sub.71)                                            77                  95                                                        88                  0.48                                                      89                  <3                                                        90                  25                                                        91                  5.70                                                      92                  1.04                                                      93                  <3                                                        94                  77.2                                                      108                 0.79                                                      109                 26.00                                                     110                 0.6                                                       114                 1.61                                                      120                 <1                                                        ______________________________________                                         *the inhibition shown in brackets was attained at this concentration.    

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by the synthetic chemicalpathways illustrated here. The synthetic chemist will readily appreciatethat the conditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by Formula 7.##STR6##

Referring now to Reaction Scheme 1 a synthetic route leading toprecursors to compounds of the invention is illustrated. In accordancewith this scheme, a 6- or 7-bromo substituted3,4-dihydro-naphthalen-1(2H)-one (numbering as shown for Compound G) ofFormula 10 is the starting material. The compounds of Formula 10 alreadycarry the desired R₁, R₂ and R₃ substituents, as these are defined abovein connection with Formula 7. The compounds of Formula 10 are reactedwith (trimethylsilyl)acetylene to provide the 6- or7-(trimethylsilyl)ethynyl-substituted 3,4-dihydro-naphthalen-1(2H)-onecompounds of Formula 11. The reaction with (trimethylsilyl)acetylene istypically conducted under heat (approximately 100° C.) in the presenceof cuprous iodide, a suitable catalyst, typically having the formulaPd(PPh₃)₂ Cl₂, an acid acceptor (such as triethylamine) under an inertgas (argon) atmosphere. Typical reaction time is approximately 24 hours.The 6- or 7-(trimethylsilyl)ethynyl-substituted3,4-dihydro-naphthalen-1(2H)-one compounds of Formula 11 are thenreacted with base (potassium hydroxide or potassium carbonate) in analcoholic solvent, such as methanol, to provide the 6- or 7-ethynylsubstituted 3,4-dihydro-1-naphthalen-1(2H)ones of Formula 12. Compoundsof Formula 12 are then coupled with the aromatic or heteroaromaticreagent X₁ -Y(R₂)-A-B' (Formula 9) in the presence of cuprous iodide, asuitable catalyst, typically Pd(PPh₃)₂ Cl₂, an acid acceptor, such astriethylamine, under inert gas (argon) atmosphere. Alternatively, a zincsalt (or other suitable metal salt) of the compounds of Formula 12 canbe coupled with the reagents of Formula 9 in the presence of Pd(PPh₃)₄or similar complex. Typically, the coupling reaction with the reagent X₁-Y(R₂)-A-B' (Formula 9) is conducted at room or moderately elevatedtemperature. Generally speaking, coupling between an ethynylarylderivative or its zinc salt and a halogen substituted aryl or heteroarylcompound, such as the reagent of Formula 9, is described in U.S. Pat.No. 5,264,456, the specification of which is expressly incorporatedherein by reference. The compounds of Formula 13 are precursors tocompounds of the invention or a derivative thereof protected in the B'group, from which the protecting group can be readily removed byreactions well known in the art. The compounds of Formula 13 can also beconverted into further precursor compounds of the invention by suchreactions and transformations which are well known in the art. Suchreactions are indicated in Reaction Scheme 1 by conversion into"homologs and derivatives". One such conversion employed for thesynthesis of several exemplary compounds of this invention issaponification of an ester group (when B or B' is an ester) to providethe free carboxylic acid or its salt.

The halogen substituted aryl or heteroaryl compounds of Formula 9 can,generally speaking, be obtained by reactions well known in the art. Anexample of such compound is ethyl 4-iodobenzoate which is obtainable,for example, by esterification of 4-iodobenzoic acid. Another example isethyl 6-iodonicotinoate which can be obtained by conducting a halogenexchange reaction on 6-chloronicotinic acid, followed by esterification.Even more generally speaking, regarding derivatization of compounds ofFormula 13 and/or the synthesis of aryl and heteroaryl compounds ofFormula 9 which can thereafter be reacted with compounds of Formula 12,the following well known and published general principles and syntheticmethodology can be employed.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of n in the compounds of Formula 9 beforeaffecting the coupling reaction of Reaction Scheme 1 (where suchcompounds corresponding to Formula 9 are not available from a commercialsource) aromatic or heteroaromatic carboxylic acids are subjected tohomologation by successive treatment under Arndt-Eistert conditions orother homologation procedures. Alternatively, derivatives which are notcarboxylic acids may also be homologated by appropriate procedures. Thehomologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

Compounds of Formula 9, (or other intermediates or of the invention, asapplicable) where A is an alkenyl group having one or more double bondscan be made for example, by synthetic schemes well known to thepracticing organic chemist; for example by Wittig and like reactions, orby introduction of a double bond by elimination of halogen from analpha-halo-arylalkylcarboxylic acid, ester or like carboxaldehyde.Compounds of Formula 9 (or other intermediates or of the invention, asapplicable) where the A group has a triple (acetylenic) bond can be madeby reaction of a corresponding aromatic methyl ketone with strong base,such as lithium diisopropylamide, reaction with diethyl chlorophosphateand subsequent addition of lithium diisopropylamide.

The acids and salts derived from compounds of Formula 13 (or otherintermediates or compounds of the invention, as applicable) are readilyobtainable from the corresponding esters. Basic saponification with analkali metal base will provide the acid. For example, an ester ofFormula 13 (or other intermediates or compounds of the invention, asapplicable) may be dissolved in a polar solvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, lithium hydroxide or potassiumhydroxide. The solution is stirred for an extended period of time,between 15 and 20 hours, cooled, acidified and the hydrolysate recoveredby conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "Advancedorganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds of Formula 9 (or other intermediates, or of the invention, asapplicable) where B is H can be prepared from the correspondinghalogenated aromatic or hetero aromatic compounds, preferably where thehalogen is I.

Referring still to Reaction Scheme 1, the7,8-dihydro-naphthalen-5(6H)-one derivatives of Formula 13 (numbering asexemplified above for Compound 1) are reduced with a mild reducing agentsuch as sodium borohydride, to yield the corresponding5-hydroxy-5,6,7,8-tetrahydronaphthalene derivatives of Formula 14. The5-hydroxy function of the compounds of Formula 14 is then acylated witha suitable acylating agent (such as a carboxylic acid chloride oranhydride), or converted into an ether with a suitable reagent (such asan alkyl bromide under basic conditions, or dihydropyran under acidicconditions) or converted into a trialkylsilyl ether (with trialkylsilylchloride or other "silylating" agent) to provide compounds of Formula15. In Formula 15 R₅ symbolizes the acyl group, or ether forming groupsuch as trialkylsilyl. The compounds of Formula 15 can be "deprotected"or otherwise converted into further precursor compounds to the inventionby reactions well known in the art, as described above.

Describing still the reactions outlined in Reaction Scheme 1, thecompounds of Formula 13 can also be reacted with a Reformatsky reagentderived from an a halocarboxylic acid ester (such as ethylbromoacetate), or with a Grignard reagent, optionally followed byacylation or ether formation on the resulting tertiary hydroxyl group onthe 5-position of the tetrahydronaphthalene nucleus, to yield compoundsof Formula 16. Alternatively, the compounds of Formula 13 are reactedwith cyanotrimethylsilane in the presence of boron trifluoroetherate toyield compounds in accordance with Formula 16. The compounds of Formula16 can also be converted into further homologs and derivatives as stillfurther precursors to compounds within the scope of the invention. InFormula 16 the R₄ group represents the group (such as alkyl, aryl orcarbalkoxyalkyl (eg CH₂ COOalkyl) which is introduced by the Grignard orReformatsky reaction.

With reference to the coupling reactions of the reagent X₁ -Y(R₂)-A-B'(Formula 9) shown in the foregoing reaction scheme, it is noted that,generally speaking, this coupling reaction can be conducted with 6- or7-substituted ethynyl compounds which either already have a substituentdesired for the present invention in the 5-position or have a precursorsuitable for introduction of such desired substituent. ##STR7##

In the preferred compounds of the invention the two R₁ substituents aremethyl, and the R₂ and R₃ substituents are hydrogen. Reaction Scheme 2illustrates a synthetic process for preparing7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) whichserves as a starting material for the synthesis of several preferredcompounds of the invention. Thus, referring now specifically to ReactionScheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterificationof 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride(DIBAL-H) to yield (3-bromophenyl)acetaldehyde.(3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with(carbethoxymethylene)triphenylphosphorane to provide a mixture of E andZ ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds arehydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D).Compound D is reacted with the Grignard reagent derived frommethylbromide to give the tertiary alcohol5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should beapparent to those skilled in the art, that the choice of the Grignardreagent used in this reaction step determines the nature of the R₁substituent in the resulting compounds of the invention.) Compound E isthen treated with acid to cyclize it and to form6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).Compound F is oxidized with chromium trioxide to yield7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G).Compound G is covered by Formula 10 and serves as a starting material inthe synthesis of several preferred compounds of the invention.

6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) isisomeric with Compound G, and can be obtained, starting with ethyl(4-bromophenyl)acetate, in accordance with the sequence of reactionsillustrated in Reaction Scheme 2 for Compound G.

6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) canalso be obtained in accordance with the published literature procedure:Mathur et al. Tetrahedron, 41, 1509-1516 (1985). Compound H is alsocovered by Formula 10 and serves as a starting material in the synthesisof several preferred compounds of the invention.

Starting materials for the synthetic routes outlined in Reaction Schemes1, 3, 4 and 5 where the R₂ and/or R₃ groups are other than hydrogen, canbe obtained similarly to the synthesis of the starting materialsdemonstrated in Reaction Scheme 2, and/or by introducing the R₂ by aFriedel-Crafts or like reaction into the aromatic portion of thetetrahydronaphthalene or dihydronaphthalene nucleus. ##STR8##

Reaction Schemes 3 and 4 disclose synthetic steps for the preparation ofthose compounds of Formula 7 where the R₂₂ group is alkyl, alkenyl,alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadlydefined in Formula 7. In accordance with the presently preferred methodof synthesizing these compounds of the invention,5-trifluoromethylsulfonyloxy 2- or 3-(aryl or heteroaryl)ethynyl7,8-dihydronaphthalene compounds of Formula 39 (numbering as exemplifiedfor Compound 1) serve as starting materials. The compounds of Formula 39can be obtained from the 5-oxo 2- or 3-(aryl or heteroaryl)ethynyl5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reaction withsodium bis(trimethylsilyl)amide and 2-N,N-bis(trifluoromethylsulfonyl)amino!-5-chloropyridine in an inertether type solvent such as tetrahydrofuran at low temperatures (-78° C.and 0° C.). This is shown above in connection with Reaction Scheme 3.

Referring now to Reaction Scheme 4 the compounds of Formula 39 arereacted with an organometal derivative derived from the alkane, alkene,alkyne, or aryl or heteroaryl compound R₂₂ H, such that the formula ofthe organometal derivative is R₂₂ Met (Met stands for metal), preferablyR₂₂ Li. The reaction with the organometal derivative, preferably lithiumderivative of the formula R₂₂ Li is usually conducted in an inert ethertype solvent (such as tetrahydrofuran) in the presence of either (1)cuprous cyanide (CuCN) and lithium chloride (LiCl), or in the presenceof zinc chloride (ZnCl₂) and tetrakis(triphenylphosphine)-palladium(0)(Pd(PPh₃)₄). The organolithium reagent R₂₂ Li, if not commerciallyavailable, can be prepared from the compound R₂₂ H (or its halogenderivative R₂₂ -X₁ where X₁ is halogen) in an ether type solvent inaccordance with known practice in the art. The temperature range for thereaction between the reagent R₂₂ Li and the compounds of Formula 39 is,generally speaking in the range of approximately -78° C. to 50° C.Examples of the lithium compounds which are used in the just describedreaction are lithium salts derived from straight and branch chainedalkanes, such as methyllithium, butyllithium, t-butyllithium, lithiumsalts derived from carbocyclic aryl compounds, such as phenyl-lithium,and lithium salts derived from heteroaryl compounds, such as2-thiazolyllithium, 2-furyllithium, 2-thienyllithium, and2-pyridyllithium. The just described synthetic process is preferablyused for the synthesis of compounds of the invention within the scope ofFormula 7 where the triple bonded (alkynyl) carbon is not directlyattached to the 5-position of the 7,8-dihydronaphthalene nucleus. Thesecompounds are shown in the scheme as the products of the reaction ofcompounds of Formula 39 with the R₂₂ Met (preferably R₂₂ Li) reagent.

Referring still to Reaction Scheme 4, the presently preferred method forthe synthesis of those compounds of Formula 7 is disclosed where atriple bonded (alkynyl) carbon is directly attached to the 5-position ofthe 7,8-dihydronaphthalene nucleus. These compounds are shown in Formula41, where R₂₃ is defined as R₂₂ of Formula 7 minus a two carbonfragment, so that the alkyne reagent R₂₃ C.tbd.CH is within theapplicable definition of R₂₂ of Formula 7; namely R₂₃ C.tbd.CH isalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, phenyl-C₁ -C₁₀alkynyl having 1 to 3 triple bonds, hydroxyalkynyl having 2 to 10carbons and 1 to 3 triple bonds, acyloxyalkynyl of 2 to 10 carbons and 1to 3 triple bonds. Compounds of Formula 41 are obtained by the reactioncompounds of Formula 39 with the reagent R₂₃ C.tbd.CH in an inert ethertype solvent, or dimethylformamide, or without solvent, in the presenceof a mild base (such as diethylamine), cuprous iodide (CuI), andbis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂ Cl₂) in aninert gas (argon) atmoshere. The reaction is typically conducted in thetemperature range of ambient to 70° C.

Compounds of Formula 40 and 41 can be converted into further homologsand derivatives still within the scope of the invention, as is describedabove in connection with compounds of Formula 13.

Referring now to Reaction Scheme 5 an alternative synthetic route forthe preparation of compounds of Formula 7 is disclosed. ##STR9##

According to this reaction scheme, derivatives of 5-hydroxy, 2- or3-(aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds ofFormula 42 serve as the starting materials. Compounds of Formula 42 canbe prepared as set forth in Reaction Scheme 1. Specifically, in Formula42 the group R₂₂ is defined as in connection with Formula 7, and R₂₄ ishydrogen, or trialkylsilyl (preferably trimethylsilyl), or any othergroup which is suitable to form a leaving group including the R₂₄ O⁻element, in the elimination reaction which is shown in the reactionscheme. The product of the elimination reaction is a compound of Formula7. The reaction is conducted under conditions which are known in the artof organic chemistry to cause formation of double bonds by elimination,for example in refluxing pyridine in the presence of excess phosphorousoxychloride (POCl₃), or in a neutral hydrocarbon type solvent (such asbenzene) in the presence of (methoxycarbonylsulfamoyl)triethylammoniumhydroxide (Burgess reagent). Reaction Scheme 5 is presently preferredfor the preparation of compounds of Formula 7 where the R₂₂ group ishydrogen, cyano (CN) and CH₂ COOEt. The elimination reaction whichresults in compounds where R₂₂ is CH₂ COOEt also gives rise to isomerswhere the double bond is exterior to the condensed 6-membered ring. Thelatter compounds are not shown in this reaction scheme.

The compounds of Formula 7 can also be prepared by first forming thedihydronaphthalene derivative substituted in the 5 position with the R₂₂group from the ketone compounds of Formula 10 (see Reaction Scheme 1)and thereafter performing the synthetic steps of replacing, the 6 or7-bromo substituents in these compounds with an ethynyl group, andsubsequently coupling the ethynyl compounds with the reagent X₁-Y(R₂)-A-B' (Formula 9).

SPECIFIC EXAMPLES

Ethyl (4-bromophenyl)acetate (Compound A)

A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g ofconc. H₂ SO₄ in 470 ml of ethanol was refluxed for 16 hours. Thereaction mixture was cooled to ambient temperature, stirred with 6 g ofsolid K₂ CO₃ for 30 minutes and then filtered. The filtrate wasconcentrated in vacuo, diluted with Et₂ O (200 ml), washed with 10%aqueous NaHCO₃ (10 ml) and brine (10 ml), dried over MgSO₄ andconcentrated in vacuo to give the title compound as a colorless oil.

PMR (CDCl₃): δ 1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).

Ethyl (3-bromophenyl)acetate (Compound B)

Employing the same general procedure as for the preparation of ethyl(4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of3-bromophenylacetic acid was converted into the title compound (yellowoil) using 2 g of conc. H₂ SO₄ and 500 ml of ethanol.

PMR (CDCl₃): δ 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).

Ethyl 4-(4-bromophenyl)butanoate (Compound C)

To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of CH₂ Cl₂ was addeddropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminumhydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition wascomplete, the reaction was stirred at -78° C. for an additional hour.The reaction was quenched by the dropwise addition of methanol (10 ml),followed by water (10 ml) and 10% HCl (40 ml). The mixture was thenwarmed to 0° C., stirred for 10 minutes and then washed with water (15ml), 10% aqueous NaHCO₃ (10 ml) and brine (10 ml). The organic phase wasdried over MgSO₄ and the solvent distilled off at ambient temperature togive crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) ofthis crude aldehyde in 150 ml of CH₂ Cl₂ was added a solution of 26 g(74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH₂Cl₂. The mixture was stirred for 16 hours, concentrated in vacuo andpurified by flash chromatography (silica, 10% EtOAc-hexane) to giveethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. Thisisomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and thefiltrate concentrated in vacuo to give the title compound as a whitesolid.

PMR (CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.88-1.99 (2H, m), 2.31 (2H, t,J=7.5 Hz), 2.61 (2H, t, J=7.5 Hz), 4.28 (2H, q, J=7.1 Hz), 7.05 (2H, d,J=8.4 Hz), 7.40(2H, d, J=8.4 Hz).

Ethyl 4-(3-bromophenyl)butanoate (Compound D)

Employing the same general multistep preparation as for ethyl4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl(3-bromophenyl)acetate (Compound B) was converted into the titlecompound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride(DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of(carbethoxymethylene)triphenylphosphorane and 1.7 g of 10% Pd/C.

PMR (CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t,J=7.5 Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz), 7.10-7.35(4H, m).

5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)

To a cold solution (0° C.) of 17 g (63 mmol) of ethyl4-(3-bromophenyl)butanoate (Compound D) in 40 ml of THF was added 63 ml(189 mmol) of methylmagnesium bromide (3.0M solution in THF). Thereaction was stirred at 0° C. for 2 hours, quenched by the slow additionof ice cold water (30 ml) followed by 10% HCl (30 ml) and then extractedwith Et₂ O (4×60 ml). The combined organic layer was washed with 10%aqueuos NaHCO₃ (10 ml), water (10 ml) and brine (10 ml), dried overMgSO₄ and concentrated in vacuo. Purification by Kugelrohr distillationgave the title compound as a colorless oil.

PMR (CDCl₃): δ 1.20 (6H, s), 1.43-1.55 (2H, m), 1.62-1.78 (2H, m), 2.60(2H, t, J=6.0 Hz), 7.10-7.41 (4H, m).

6-Bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F)

15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methyl- pentan-2-ol (CompoundE) was cooled to 0° C. and then 2.8 ml of conc. H₂ SO₄ was added. Themixture was stirred for 2.5 hours, diluted with water (20 ml) andextracted with Et₂ O (3×40 ml). The combined organic layers were washedwith water, sat. aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. Purification by Kugelrohr distillation gave thetitle compound as a colorless oil.

PMR (CDCl₃): δ 1.25 (6H, s), 1.61-1.66 (2H, m), 1.74-1.82 (2H, m), 2.73(2H, t, J=6.0 Hz), 7.16-7.26 (3H, m).

7-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G)

To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acidwas added a solution of 10 g (41.8 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125ml of benzene. The reaction mixture was stirred for 1 hour, quenchedwith ice cold water and extracted with Et₂ O (3×100 ml). The organiclayer was dried over MgSO₄, concentrated in vacuo, and purified bycolumn chromatography (silica, 10% EtOAc-hexane) to give the titlecompound as a white solid.

PMR (CDCl₃): δ 1.28 (6H, s), 2.01 (2H, t, J=6.0 Hz), 2.72 (2H, t, J=6.0Hz), 7.31 (1H, d, J=9.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 8.11 (1H, d,J=3.0 Hz).

6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H)

Employing a published procedure (Mathur, N. C.; Snow, M. S.; Young, K.M.; and Pincock, J. A. Tetrahedron, 41, 1509-1516 (1985) ), ethyl4-(4-bromophenyl)butanoate (Compound C) was converted into the titlecompound. Alternatively, the title compound can be obtained usingsimilar reactions that were used to convert ethyl4-(3-bromophenyl)butanoate (Compound D) into7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G).

6-Ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K)

To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g(53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) ofcuprous iodide. The solution mixture was flushed with argon for 5minutes and then 100 ml (938.7 mmol) of (trimethylsilyl)acetylene wasadded. The reaction mixture was sealed in a pressure tube and placed ina preheated oil bath (100° C.) for 24 hours. The reaction mixture wasthen filtered through Celite, washed with Et₂ O and the filtrateconcentrated in vacuo to give crude6-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one.To a solution of this crude TMS-acetylenic compound in 50 ml of methanolwas added 2.8 g (20.3 mmol) of K₂ CO₃. The mixture was stirred for 8hours at ambient temperature and then filtered. The filtrate wasconcentrated in vacuo, diluted with Et₂ O (100 ml), washed with water(10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO₄ andconcentrated in vacuo. Purification by column chromatography (silica,10% EtoAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ 1.38 (6H, s), 2.01 (2H, t, J=7.1 Hz), 2.72 (2H, t, J=7.1Hz), 3.24 (1H, s), 7.39 (1H, dd, J=1.5, 8.1 Hz), 7.54 (1H, d, J=1.5 Hz),7.91 (1H, d, J=8.1 Hz).

7-Ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 7 g(27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) was converted into the title compound using 39 ml (36.6mmol) of (trimethylsilyl)acetylene, 0.97 g (1.3 mmol) ofbis(triphenylphosphine)palladium(II) chloride, 0.26 g (1.3 mmol) ofcuprous iodide and 0.6 g (4.3 mmol) of K₂ CO₃.

PMR (CDCl₃): δ 1.39 (6H, s), 2.02 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0Hz), 3.08 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.61 (1H, dd, J=1.8, 8.2 Hz),8.14 (1H, d, J=9 1.8 Hz).

Ethyl-4-iodobenzoate

To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 mlabsolute ethanol was added 2 ml thionyl chloride and the mixture wasthen heated at reflux for 3 hours. Solvent was removed in vacuo and theresidue was dissolved in 100 ml ether. The ether solution was washedwith saturated NaHCO₃ and saturated NaCl solutions and dried (MgSO₄).Solvent was then removed in vacuo and the residue Kugelrohr distilled(100 degrees C.; 0.55 mm) to give the title compound as a colorless oil,PMR (CDCl₃): δ 1.42 (3H, t, J-7 Hz), 4,4 (2H, q, J-7 Hz), 7.8 (4H).

Ethyl 6-chloronicotinate

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 gdimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand the residue subjected to flash chromatography to give the titlecompound as a low-melting white solid. PMR (CDCl₃): δ 1.44 (3H, t, J-6.2Hz) 4.44 (2H, q, J-4.4 Hz), 7.44 (1H, d, J-8.1 Hz), 8.27 (1H, dd, J-8.1Hz, 3 Hz), 9.02 (1H, d, J-3 Hz).

6-Iodonicotinic acid

To 27.97 g (186.6 mmol) of sodium iodide cooled to -78° C. was added121.77 g (71.6 ml, 952.0 mmol) of hydriodic acid (57 wt %). The reactionmixture was allowed to warm slightly with stirring for 5 minutes, andthen 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. Theresulting mixture was allowed to warm to room temperature with stirringand then heated at 120°-125° C. in an oil bath for 42 hours. A darkbrown layer formed above the yellow solid material. The reaction mixturewas allowed to cool to room temperature and then poured into acetone(chilled to 0° C.). The resultant yellow solid was collected byfiltration, washed with 200 ml of 1N NaHSO₃ solution, and dried in highvacuum (3 mm Hg) to give the title compound as a pale yellow solid.

PMR (DMSO-d₆): δ 7.90 (1H, dd, J=8.1, 2 Hz), 7.99 (1H, d, J=8.1 Hz),8.80 (1H, d, J=2. Hz).

Ethyl 6-iodonicotinate

To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 mlof dichloromethane was added a solution of 19.86 g (103.6 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 250 ml ofdichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine.The resulting solution mixture was then heated at 50° C. in an oil bathfor 24.5 hours, concentrated in vacuo, partitioned between 200 ml ofwater and 250 ml of ethyl ether, and the layers were separated. Theaqueous phase was washed with 2×150 ml-portions of ethyl ether. Allorganic phases were combined, washed once with 75 ml of brine solution,dried over MgSO₄, filtered and concentrated in vacuo to a yellow solid.Purification by flash chromatography (silica, 10% ethyl acetate inhexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ 1.41 (3H, t, J=7.1 Hz), 4.41 (2H, q, J=7.1 Hz), 7.85 (1H,d, J=8.2 Hz), 7.91 (1H, dd, J=8.2, 2.1 Hz), 8.94 (1H, d, J=2.1 Hz).

Ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1)

To a solution of 8.8 g (47.8 mmol) of6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K)flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) ofethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.30 g (1.6mmol) of cuprous iodide. The solution mixture was flushed with argon for5 minutes and then stirred at ambient temperature for 18 hours. Thereaction mixture was filtered through Celite and the filtrateconcentrated in vacuo. Purification by flash chromatography (silica, 10%EtOAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ 1.41 (3H, t, J=7.2 Hz), 1.43 (6H, s), 2.04 (2H, t, J=7.0Hz), 2.75 (2H, t, J=7.0 Hz), 4.40 (2H, q, J=7.2 Hz), 7.46 (1H, dd,J=1.5, 8.1 Hz), 7.60 (1H, d, J=1.5 Hz), 7.63 (2H, d, J=8.4 Hz), 8.01(1H, d, J=8.1 Hz), 8.05 (2H, d, J=8.4 Hz).

Ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoate(Compound 2)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1), 4 g (21.7 mmol) of7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) wasconverted into the title compound using 6 g (21.7 mmol) of ethyl4-iodobenzoate, 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II)chloride and 1.4 g (7.2 mmol) of cuprous iodide.

PMR (CDCl₃): δ 1.41 (3H, t, J=7.2 Hz), 1.41 (6H, s), 2.04 (2H, t, J=6.5Hz), 2.76 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=8.2Hz), 7.59 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=1.8, 8.2 Hz), 8.04 (2H, d,J=8.4 Hz), 8.15 (1H, d, J=1.8 Hz).

Ethyl 6-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!nicotinate(Compound 3)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1), 606 mg (3.48 mmol) of7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K) wasconverted into the title compound using 964 mg (3.48 mmol) of ethyl6-iodonicotinate, 122 mg (0.17 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 9.5 mg (0.17 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.41 (6H, s), 1.43 (3H, t, J=7.1 Hz), 2.05 (2H, t, J=7.1Hz), 2.76 (2H, t, J=7.1 Hz), 4.43 (2H, q, J=7.1 Hz), 7.46 (1H, d, J=8.2Hz), 7.60 (1H, d, J=7.8 Hz), 7.75 (1H, dd, J=1.9, 8.2 Hz), 8.27 (1H, d,J=1.9 Hz), 8.30 (1H, dd, J=2.0, 7.8 Hz), 9.22 (1H, br s).

Ethyl 6-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!nicotinate(Compound 5)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1), 422 mg (2.1 mmol) of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) wasconverted into the title compound using 202 mg (0.73 mmol) of ethyl6-iodonicotinate, 168 mg (0.24 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 45.7 mg (0.24 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.40 (6H, s), 1.42 (3H, t, J=7.1 Hz), 2.04 (2H, t, J=6.0Hz), 2.74 (2H, t, J=6.0 Hz), 4.43 (2H, q, J=7.1 Hz), 7.51 (1H, d, J=8.4Hz), 7.63 (1H, d, J=8.4 Hz), 7.70 (1H, s), 8.01 (1H, d, J=8.1 Hz), 8.30(1H, d, J=8.1 Hz), 9.22 (1H, s).

4- (5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoicacid (Compound 7)

To a suspension of 0.30 g (0.87 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1) in 4 ml of THF and 2 ml of ethanol was added 2 ml (2 mmol)of LiOH (1N aqueous solution). The reaction mixture was stirred at roomtemperature for 4 hours, concentrated in vacuo to near dryness,partitioned between EtOAc and 1 ml of water and acidified to pH 4 with10% HCl. The aqueous layer was extracted with EtOAc and then the organiclayer was dried over Na₂ SO₄ and concentrated in vacuo to give the titlecompound as a light yellow solid.

PMR (DMSO-d₆): δ 1.39 (6H, s), 1.98 (2H, t, J=7.0 Hz), 2.70 (2H, t,J=7.0 Hz), 7.54 (1H, dd, J=1.5 8.1 Hz), 7.73 (2H, d, J=8.4 Hz), 7.77(1H, d, J=1.5 Hz), 7.90 (1H, d, J=8.1 Hz), 8.00 (2H, d, J=8.4 Hz).

4- (5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl benzoicacid (Compound 8)

Employing the same general procedure as for the preparation of4-((5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoicacid (Compound 7), 500 mg (1.45 mmol) of ethyl4-((5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoate(Compound 2) was converted into the title compound using 4 ml (4 mmol)of LiOH (1N aqueous solution).

PMR (DMSO-d₆): δ 1.37 (6H, s), 1.99 (2H, t, J=6.9 Hz), 2.71 (2H, t,J=6.9 Hz), 7.64 (1H, d, J=8.2 Hz), 7.70 (2H, d, J=8.3 Hz), 7.80 (1H, dd,J=2.0, 8.2 Hz), 7.98 (3H, m).

Ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynl!benzoate(Compound 9)

To a cold solution (0° C.) of 980 mg (2.8 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1) in 5 ml of THF and 10 ml of ethanol was added 78 mg (2mmol) of sodium borohydride. The mixture was stirred for 6 hours,diluted with water (10 ml) and extracted with Et₂ O (4×40 ml). Thecombined organic layers were washed with 10% HCl (5 ml), 10% aqueousNaHCO₃ (10 ml) and brine (10 ml), dried over MgSO4 and concentrated invacuo to give the title compound as a white solid.

PMR (CDCl₃): δ 1.25 (3H, s), 1.32 (3H, s), 1.38 (3H, t, J=7.2 Hz),1.56-1.65 (1H, m),1.78-2.15 (4H, m), 4.35 (2H, q, J=7.2 Hz), 4.70 (1H,q, J=4.0 Hz), 7.33 (1H, dd, J=1.5, 8.1 Hz), 7.41 (1H, d, J=8.1 Hz), 7.49(1H, d, J=1.5 Hz), 7.56 (2H, d, J=8.4 Hz), 7.98 (2H, d, J=8.4 Hz).

Ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 10)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 9), 1 g (2.88 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoate(Compound 2) was converted into the title compound using 60 mg (1.6mmol) of sodium borohydride.

PMR (CDCl₃): δ 1.26 (3H, s), 1.33 (3H, s), 1.40 (3H, t, J=7.1 Hz),1.58-1.70 (1H, m), 1.80-1.95 (2H, m), 2.04-2.14 (1H, m), 4.38 (2H, q,J=7.1 Hz), 4.72 (1H, q, J=5.1 Hz), 7.32 (1H, d, J=8.2 Hz), 7.41 (1H, dd,J=1.8, 8.2 Hz), 7.56 (2H, d, J=8.5 Hz), 7.65 (1H, d, J=1.8 Hz), 8.01(2H, d, J=8.5 Hz).

Ethyl 6-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl!nicotinate(Compound 11)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 9), 700 mg (2 mmol) of ethyl 6-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!nicotinate(Compound 4) was converted into the title compound using 60 mg (1.6mmol) of sodium borohydride.

PMR (CDCl₃): δ 1.26 (3H, s), 1.33 (3H, s), 1.42 (3H, t, J=7.1 Hz),1.52-1.70 (1H, m), 1.70-1.95 (2H, m), 2.10-2.20 (1H, m), 4.40 (2H, q,J=7.1 Hz), 4.70 (1H, br s), 7.32 (1H, d, J=8.0 Hz), 7.48 (1H, d, J=7.9Hz), 7.55 (1H, d, J=8.0 Hz), 7.84 (1H, s), 8.28 (1H, d, J=7.9 Hz), 9.20(1H, br s).

4- (5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl!benzoicacid (Compound 41)

Employing the same general procedure as for the preparation of 4-5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl!ethynyl!benzoicacid (Compound 32), 272 mg (0.78 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 10) was converted into the title compound using 2 ml (2 mmol)of LiOH (1M aqueous solution).

PMR (acetone-d₆): δ 1.28 (3H, s), 1.31 (3H, s), 1.60-1.70 (1H, m),1.80-1.96 (2H, m), 2.00-2.12 (1H, m), 4.67 (1H, t, J=7.1 Hz), 7.42 (2H,br s), 7.67 (1H, d, J=8.2 Hz), 7.69 (1H, br s), 8.07 (2H, d, J=8.2 Hz).

4- (5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl!benzoicacid (Compound 42)

110 mg (0.31 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 9) in a mixture of THF and methanol was refluxed with 1 ml (1mmol) of LiOH (1M aqueous solution). Thereafter the mixture was dilutedwith Et₂ O:EtOA_(c) (1:1), and acidified with aqueous HCl to pH5. Theorganic phase was separated, washed (water and brine), dried (MgSO₄) toyield the title compound.

PMR (acetone-d₆): δ 1.28 (3H, s), 1.31 (3H, s), 1.58-1.70 (1H, m),1.76-1.92 (2H, m), 1.98-2.10 (1H, m), 4.66 (1H, t, J=5.1 Hz), 7.35 (1H,dd, J=1.6, 7.9 Hz), 7.53 (1H, d, J=7.9 Hz), 7.65 (2H, d, J=8.1 Hz), 8.05(2H, d, J=8.1 Hz).

6- (5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!nicotinicacid (Compound 44)

Employing the same general procedure as for the preparation of 4-5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl!ethynyl!benzoic acid(Compound 7), 300 mg (0.86 mmol) of ethyl 6-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!nicotinate(Compound 3) was converted into the title compound (pale yellow solid)using 8.6 ml (8.6 mmol) of LiOH (1M aqueous solution).

PMR (DMSO-d₆): PMR δ 1.38 (6H, s), 1.99 (2H, t, J=6 Hz), 2.72 (2H, t,J=6 Hz), 7.68 (1H, d, J=8.2 Hz), 7.82 (1H, d, J=8.5 Hz), 7.86 (1H, dd,J=2, 8.2 Hz), 8.04 (1H, d, J=2 Hz), 8.30 (1H, dd, J=1.9, 7.9 Hz), 9.07(1H, d, 1.9 Hz).

Ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66)

To a cold solution (-78° C.) of 291.6 mg (1.59 mmol) of sodiumbis(trimethylsily)amide in 5.6 ml of THF was added a solution of 500.0mg (1.44 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoate(Compound 2) in 4.0 ml of THF. The reaction mixture was stirred at -78°C. for 35 minutes and then a solution of 601.2 mg (1.59 mmol) of 2-N,N-bis(trifluoromethylsulfonyl)amino!-5-chloropyridine in 4.0 ml of THFwas added. After stirring at -78° C. for 1 hour, the solution was warmedto 0° C. and stirred for 2 hours. The reaction was quenched by theaddition of sat. aqueous NH₄ Cl. The mixture was extracted with EtOAc(50 ml) and the combined organic layers were washed with 5% aqueousNaOH, water, and brine. The organic phase was dried over Na₂ SO₄ andthen concentrated in vacuo to a yellow oil. Purification by columnchromatography (silica, 7% EtOAc-hexanes) yielded the title compound asa colorless waxy solid.

PMR (CDCl₃): δ 1.33 (6H, s), 1.43 (3H, t, J 7.1 Hz), 2.44 (2H, d, J=5.0Hz), 4.40 (2H, q, J=7.1 Hz), 6.02 (1H, t, J=5.0 Hz), 7.32 (1H, d, J=8.0Hz), 7.51 (2H, m), 7.60 (2H, dd, J=1.8, 8.4 Hz), 8.04 (2H, dd, J=1.8,8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67)

A solution of 2-lithiothiazole was prepared by the addition of 41.2 mg(0.42 ml, 0.63 mmol) of n-butyl-lithium (1.5M solution in hexanes) to acold solution (-78° C.) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml ofTHF. The solution was stirred at for 30 minutes and then a solution of113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added. Theresulting solution was warmed to room temperature, stirred for 30minutes and then the organozinc was added via cannula to a solution of200.0 mg (0.42 mmol) of ethyl 4-(8-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) and 12.4 mg (0.01 mmol) oftetrakis(triphenylphosphine)palladium(0) in 1.5 ml of THF. The resultingsolution was heated at 50° C. for 45 minutes, cooled to room temperatureand diluted with sat. aqueous NH₄ Cl. The mixture was extracted withEtOAc (40 ml) and the combined organic layers were washed with water andbrine. The organic phase was dried over Na₂ SO₄ and concentrated invacuo to a yellow oil. Purification by column chromatography (silica,20% EtOAc-hexanes) yielded the title compound as a colorless oil.

PMR (CDCl₃): δ 1.35 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.42 (2H, d, J=4.8Hz), 4.38 (2H, q, J=7.1 Hz), 6.57 (1H, t, J=4.8 Hz), 7.33 (1H, d, J=3.3Hz), 7.36 (1H, d, J=8.0 Hz), 7.46 (1H, dd, J=1.7, 8.1 Hz), 7.55 (2H, d,J=8.4 Hz), 7.87 (1H, d, J=1.7 Hz), 7.92 (1H, d, J=3.3 Hz), 8.00 (2H, d,J=8.4 Hz).

Ethyl 4- (7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl!benzoate(Compound 68)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 203.8 mg (0.43 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(compound 66) was converted into the title compound (colorless solid)using 58.2 mg (0.36 ml, 0.69 mmol) of phenyllithium (1.8M solution incyclohexane/Et₂ O), 116.1 mg (0.85 mmol) of zinc chloride and 13.8 mg(0.01 mmol) of tetrakis(triphenylphosphine)palladium(0).

PMR (CDCl₃): δ 1.36 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.37 (2H, d, J=4.7Hz), 4.38 (2H, q, J=7.1 Hz), 6.02 (1H, t, J=4.7 Hz), 7.20 (1H, d, J=1.5Hz), 7.27 (1H, m), 7.39 (6H, m), 7.52 (2H, d, J=8.2 Hz), 7.98 (2H, d,J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(4-(1,1-dimethylethyl)phenyl)naphth-3-yl)ethynyl!benzoate(Compound 69)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (colorless solid)using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) oftetrakis(triphenylphosphine)palladium(0) and 4-tert-butylphenyllithium(prepared by adding 100.6 mg (0.97 mL, 1.57 mmol) of tert-butyllithium(1.5M solution in pentane) to a cold solution (-78° C.) of 167.0 mg(0.78 mmol) of 4-tert-butylbromobenzene in 1.0 mL of THF).

PMR (CDCl₃): δ 1.35 (6H, s), 1.39 (9H, s), 1.40 (3H, t, J=7.2 Hz), 1.59(3H, s), 2.36 (2H, d, J=4.9 Hz), 4.38 (2H, q, J=7.2 Hz), 6.02 (1H, t,J=4.9 Hz), 7.28-7.45 (7H, m), 7.55 (2H, d, J=8.4 Hz), 7.99 (2H, d, J=8.4Hz).

Ethyl4-(7,8-dihydro-8,8-dimethyl-5-(2-pyridyl)naphth-3-yl)ethynyllbenzoate(Compound 70)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl!benzoate(Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (colorless solid)using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) oftetrakis(triphenylphosphine)palladium(0) and 2-lithiopyridine (preparedby the addition of 100.6 mg (0.97 ml, 1.57 mmol) of tert-butyllithium(1.5M solution in pentane) to a cold solution (-78° C.) of 123.8 mg(0.784 mmol) of 2-bromopyridine in 1.0 mL of THF).

PMR (d₆ -acetone): δ 1.35 (6H, s), 1.35 (3H, t, J=7.1 Hz), 2.42 (2H, d,J=4.7 Hz), 4.34 (2H, q, J=7.1 Hz), 6.32 (1H, t, J=4.7 Hz), 7.35 (2H, m),7.47 (2H, d, J=1.1 Hz), 7.50 (1H, d, J=7.7 Hz), 7.58 (2H, d, J=8.4 Hz),7.85 (1H, ddd, J=1.8, 7.7, 9.5 Hz), 7.99 (2H, d, J=8.4 Hz), 8.64 (1H,m).

Ethyl 4- (7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-ylethynyl!benzoate (Compound 71)

and Ethyl 4- (7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 72)

A mixture of 35.1 mg (0.39 mmol) of cuprous cyanide and 16.6 mg (0.39mmol) of lithium chloride was flame dried under vacuum, cooled to roomtemperature and dissolved in 1.5 ml of THF. This solution was cooled to-78° C. and 50.2 mg (0.46 mL, 0.784 mmol) of tert-butyllithium (1.7Msolution in pentane) was added forming a clear yellow solution. Thereaction mixture was stirred at -78° C. for 15 minutes and then 125.0 mg(0.26 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was added as a solution in 0.5 ml of THF. After 10 minutesthe reaction was quenched at -78° C. with 1.5 ml of a 2:1 (v/v) mixtureof sat. aqueous NH₄ Cl and 5% NaOH. The mixture was extracted with EtOAcand the combined organic layers were washed with water and brine. Theorganic phase was dried over MgSO₄, concentrated in vacuo and purifiedby column chromatography (silica, 5% EtOAc-hexanes) to give a clearyellow oil (7:5 ratio of title compounds). The two compounds wereseparated by HPLC (partisil 10, 2% EtOAc-hexanes) to give the titlecompounds as colorless oils.

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71)

PMR (CDCl₃): δ 1.23 (6H, s), 1.39 (9H, s), 1.42 (3H, t J=7.2 Hz), 2.16(2H, d, J=4.9 Hz), 4.40 (2H, q, J=7.2 Hz), 6.01 (1H, t, J=4.9 Hz), 7.34(2H, m, J=1.6, 7.3 Hz), 7.61 (2H, d, J=8.2 Hz), 7.81 (1H, d, J=1.6 Hz),8.03 (2H, d, J=8.2 Hz).

Ethyl 4- (7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate (Compound72)

PMR (CDCl₃): δ 1.28 (6H, s), 1.43 (3H, t, J=7.2 Hz), 2.27 (2H, dd,J=1.9, 4.4 Hz), 4.39 (2H, q, J=7.2 Hz), 5.99 (1H, dt, J=4.4, 9.3 Hz),6.44 (1H, dt, J=1.9, 9.3 Hz), 7.22 (1H, d, J=1.3 Hz), 7.26-7.39 (2H, m),7.57 (2H, d, J=8.4 Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl 4- (7,8-dihydro-5,8,8-trimethylnaphth-3-yl)ethynyl!benzoate(Compound 73)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71), 250 mg (0.52 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (HPLC Partisil 10,0.5% EtOAC-hexanes) using 70.2 mg (0.78 mmol) of cuprous cyanide, 33.2mg (0.78 mmol) of lithium chloride and 34.5 mg (1.28 ml, 1.57 mmol) ofmethyllithium (1.22M solution in Et₂ O).

PMR (CDCl₃): δ 1.27 (6H, s), 1.41 (3H, t, J=7.1 Hz), 2.09 (3H, d, J=1.7Hz), 2.21 (2H, dd, J=1.8, 4.1 Hz), 4.39 (2H, q, J=7.1 Hz), 5.82 (1H, brm), 7.30 (1H, d, J=7.7 Hz), 7.40 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=7.3Hz), 8.03 (2H, d, J=8.3 Hz).

4- (5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 74)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71), 98.1 mg (0.205 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (HPLC Partisil 10,1% tBuOMe-hexanes) using a mixture of 27.5 mg (0.31 mmol) of cuprouscyanide and 13.0 mg (0.31 mmol) of lithium chloride in 1.5 ml of Et₂ Otreated with 39.4 mg (0.41 ml, 0.62 mmol) of n-butyllithium (1.5Msolution in hexane).

PMR (CDCl₃): δ 0.96 (3H, t), 1.26 (6H, s), 1.42 (3H, t, J=7.1 Hz), 1.43(2H, m), 1.55 (2H, m), 2.20 (2H, d, J=4.5 Hz), 2.47 (2H, t, J=6.5 Hz),4.39 (2H, q, J=7.1 Hz), 5.80 (1H, t, J=4.5 Hz), 7.31 (1H, d, J=8.0 Hz),7.39 (1H, dd, J=1.8, 8.0 Hz), 7.43 (1H, br s), 7.61 (2H, d, J=8.2 Hz),8.03 (2H, d, J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75)

A solution (flushed with argon) of 201.3 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66), 286.5 mg (4.21 mmol) of 1-pentyne, 59.5 mg (0.08 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 32.0 mg (0.17 mmol) ofcuprous iodide in 2.5 ml of diethylamine was heated to 70° C. in apressure vial for 6 hours. After stirring overnight at room temperature,the mixture was diluted with EtOAc (25 ml) and washed with water andbrine. The organic phase was dried over MgSO₄, concentrated in vacuo andpurified by column chromatography (silica, 5% Et₂ O-hexanes) to give thetitle compound as a colorless, air-sensitive oil.

PMR (CDCl₃): δ 1.10 (3H, t, J=7.2 Hz), 1.28 (6H, s), 1.42 (3H, t, J=7.2Hz), 1.69 (2H, sextet, J=7.2 Hz), 2.31 (2H, d, J=4.7 Hz), 2.46 (2H, t,J=7.0 Hz), 4.39 (2H, q, J=7.2 Hz), 6.35 (1H, t, J=4.7 Hz), 7.30 (1H, s),7.42 (1H, dd, J=1.5, 7.8 Hz), 7.59 (2H, d, J=8.3 Hz), 7.82 (1H, d, J=1.5Hz), 8.03 (2H, d, J=8.3 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl!benzoate(Compound 76)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 184.3 mg (0.39 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethyl-naphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (pale yellow oil)using 316.4 mg (3.85 mmol) 3,3-dimethyl-1-butyne, 54.5 mg (0.08 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 29.3 mg (0.15 mmol) ofcuprous iodide. PMR (CDCl₃): δ 1.28 (6H, s), 1.39 (9H, s), 1.41 (3H, t,J=7.2 Hz) 2.31 (2H, d, J=4.9 Hz), 4.39 (2H, q, J=7.2 Hz), 6.33 (1H, t,J=4.9 Hz), 7.29 (1H, s), 7.41 (1H, dd, J=1.7, 8.0 Hz), 7.59 (2H, d,J=8.4 Hz), 7.76 (1H, d, J=1.7 Hz), 8.03 (2H, d, J=8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)-naphth-3-yl)ethynyl!benzoate(Compound 77)

Into a solution of 263.7 mg (0.55 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66), 4.2 mg (0.02 mmol) cuprous iodide and 7.8 mg (0.11 mmol)bis(triphenylphosphine)palladium(II) chloride in 2.0 ml of DMF and 1.0ml of diethylamine was bubbled propyne. The initial blue solution turnedbrown in color after 45 minutes of stirring at room temperature. Thereaction mixture was diluted with EtOAc (40 ml) and washed with waterand brine. The organic phase was dried over MgSO₄, concentrated in vacuoand purified by column chromatography (silica, 5% Et₂ O-hexanes) to givethe title compound as a colorless solid.

PMR (CDCl₃): δ 1.38 (6H, s), 1.42 (3H, t, J=7.2 Hz), 2.12 (3H, s), 2.31(2H, d, J=4.8 Hz), 4.40 (2H, q, J=7.2 Hz), 6.34 (1H, t, J=4.8 Hz), 7.30(1H, s), 7.42 (1H, dd, J=1.5, 7.6 Hz), 7.61 (2H, d, J=8.6 Hz) 7.78 (1H,d, J=1.5 Hz), 8.03 (2H, d, J=8.6 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoicacid (Compound 78)

A solution of 33.9 mg (0.08 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67) and 8.5 mg (0.20 mmol) of LiOH-H₂ O in 3 ml of THF/water(3:1, v/v), was stirred overnight at room temperature. The reaction wasquenched by the addition of sat. aqueous NH₄ Cl and extracted withEtOAc. The combined organic layers were washed with water and brine,dried over Na₂ SO₄ and concentrated in vacuo to give the title compoundas a colorless solid.

PMR (d₆ -DMSO): δ 1.29 (6H, s), 2.42 (2H, d, J=4.6 Hz), 6.68 (1H, t,J=4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J=8.2 Hz), 7.77 (1H, d, J=3.3 Hz),7.93 (2H, d, J=8.2 Hz), 7.98 (1H, d, J=3.3 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 79)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoicacid (Compound 78), 27.0 mg (0.07 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl!benzoate (Compound68) was converted into the title compound (colorless solid) using 5.9 mg(0.14 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.31 (6H, s), 2.35 (2H, d, J=4.5 Hz), 6.05 (1H, t,J=4.5 Hz), 7.00 (1H, s), 7.33 (2H, d, J=6.2 Hz), 7.44 (4H, m), 7.59 (2H,d, J=8.1 Hz), 7.90 (2H, d, J=8.1 Hz).

4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoicacid (Compound 80)

A solution of 24.0 mg (0.06 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H₂ 0 in 3 mL THF/water(3:1, v/v) was stirred overnight (22 hours) at room temperature. Thereaction mixture was extracted with Et₂ O and the layers were separated.The aqueous layer was acidified with HCl (1M aqueous solution) and thenextracted with EtOAc. The organic phase was dried over Na₂ SO₄ andconcentrated in vacuo to give the title compound as a colorless solid.

PMR (d₆ -DMSO): δ 1.23 (6H, s), 1.37 (9H, s), 2.16 (2H, d, J=4.9 q 1Hz),6.07 (1H, t, J=4.9 Hz), 7.40 (2H, s), 7.66 (2H, d, J=8.1 Hz), 7.84(1H,s), 8.06 (2H, d, J=8.1 Hz).

4- (7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoic acid (Compound81)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoicacid (Compound 80), 25.3 mg (0.08 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate (Compound 72) wasconverted into the title compound (colorless solid) using 8.0 mg (0.14mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.26 (6H, s), 2.27 (2H, dd, J=2.9, 4.4 Hz), 6.03 (1H,dt, J=4.4, 9.6 Hz), 6.51 (1H, ddd, J=1.9, 3.6, 9.6 Hz), 7.27 (1H, s),7.39 (2H, m), 7.67 (2H, d, J=7.6 Hz), 8.07 (2H, J=7.6 Hz).

4- (5,8,8-trimethyl-7,8-dihydronaphth-3-yl)ethynyl!benzoic acid(Compound 82)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoicacid (Compound 80), 33.7 mg (0.10 mmol) of ethyl 4-(7,8-dihydro-5,8,8-trimethylnaphth-3-yl)ethynyl!benzoate (Compound 73)was converted into the title compound (colorless solid) using 10.2 mg(0.25 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.22 (6H, s), 2.06 (3H, d, J=1.4 Hz), 2.18 (2H, dd,J=2.1, 4.5 Hz), 5.87 (1H, br m), 7.42 (3H, m), 7.67 (2H, d, J=8.4 Hz),7.97 (2H, d, J=8.4 Hz).

4- (5-butyl-8,8-dimethyl-7,8-dihydronaphth-3-yl)ethynyl!benzoic acid(Compound 83)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoicacid (Compound 80), 22.6 mg (0.06 mmol) of ethyl 4-(5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)-ethynyl!benzoate (Compound74) was converted into the title compound using 6.1 mg (0.146 mmol) ofLiOH in H₂ O.

PMR (d₆ -DMSO): δ 0.90 (3H, t, J=7.1 Hz), 1.20 (6H, s), 1.35 (2H, m),1.45 (2H, m), 2.16 (2H, d, J=4.2 Hz), 2.43 (2H, t), 5.82 (1H, t, J=4.2Hz), 7.36 (1H, m), 7.43 (2H, d), 7.84 (2H, d).

4- (7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoicacid (Compound 84)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoicacid (Compound 80), 42.0 mg (0.106 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75) was converted into the title compound (colorless solid)using 11.1 mg (0.27 mmol) of LiOH in H₂ O in 3 mL of THF/water (3:1,v/v, flushed with argon).

PMR (d₆ -DMSO): δ 1.04 (3H, br t), 1.22 (6H, s), 1.59 (2H, m), 2.30 (2H,m), 2.45 (2H, m), 6.37 (1H, br t), 7.38 (1H, m), 7.48 (1H, m), 7.60 (2H,d, J=7.4 Hz), 7.67 (1H, s), 7.96 2H, d, J=7.4 Hz).

4-(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl!benzoicacid (Compound 85)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoic acid(Compound 84), 34.7 mg (0.085 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl!benzoate(Compound 76) was converted into the title compound (colorless solid)using 9.6 mg (0.23 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.21 (6H, s), 1.32 (9H, s), 2.29 (2H, d, J=4.8 Hz),6.34 (1H, t, J=4.8 Hz), 7.39 (1H, d, J=8.0 Hz), 7.48 (1H, dd, J=1.8, 8.0Hz), 7.61 (1H, d, J=1.8 Hz), 7.65 (2H, d, J=8.3 Hz), 7.96 (2H, d, J=8.3Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl!benzoicacid (Compound 86)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoic acid(Compound 84), 75.0 mg (0.204 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl!benzoate(Compound 77) was converted into the title compound (colorless solid)using 21.4 mg (0.51 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.22 (6H, s), 2.10 (3H, s), 2.30 (2H, d, J=4.5 Hz),6.38 (1H, t, J=4.5 Hz), 7.39 (2H, d, J=8.2 Hz), 7.47 (2H, d, J=7.7 Hz),7.54 (2H, d, J=7.7 Hz), 7.61 (1H, s), 7.89 (2H, d, J=7.7 Hz).

Ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87)

Employing the same general procedure as for the preparation of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66), 800 mg (2.31 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1) in 2 ml of THF was converted into the title compound (whitesolid) using 466 mg (2.5 ml, 2.54 mmol) of sodiumbis(trimethylsilyl)amide (1.0M solution in THF) and a solution of 961 mg(2.54 mmol) of 2-N,N-bis(trifluoromethylsulfonyloxy)amino!-5-chloropyridine in 2 ml ofTHF.

PMR (CDCl₃): δ 1.34 (6H, s), 1.41 (3H, t, J=7.2 Hz), 2.44 (2H, d, J=4.8Hz), 4.39 (2H, q, J=7.2 Hz), 6.01 (1H, t, J=4.8 Hz), 7.37 (1H, d, J=8.0Hz), 7.45 (1H, dd, J=1.5, 8.0 Hz), 7.48 (1H, d, J=1.5 Hz), 7.60 (2H, d,J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl!benzoate(Compound 88)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 400 mg (0.84 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) in 2 ml of THF was converted into the title compound(white solid) using a solution of 82 mg (1.26 mmol) of thiazole in 2 mlof THF, 81 mg (0.84 ml, 1.26 mmol) of n-butyllithium (1.5M solution inhexanes), 228 mg (3.36 ml, 1.68 mmol) of zinc chloride (0.5M solution inTHF) and 10 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium (0).

PMR (CDCl₃): δ 1.36 (6H, s), 1.41 (3H, t, J=7.2 Hz), 2.42 (2H, d, J=4.9Hz), 4.39 (2H, q, J=7.2 Hz), 6.58 (1H, t, J=4.9 Hz), 7.32 (1H, d, J=3.4Hz), 7.38 (1H, dd, J=1.7, 8.1 Hz), 7.54 (1H, d, J=1.7 Hz), 7.60 (2H, d,J=8.2 Hz), 7.72 (1H, d, J=8.1 Hz), 7.87 (1H, d, J=3.4 Hz), 8.02 (2H, d,J=8.2 Hz).

Ethyl 4- (7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoate(Compound 89)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy)-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) in 1 ml of THF was converted into the title compound(white solid) using 53 mg (0.35 ml, 0.63 mmol) of phenyllithium (1.8M incyclohexane/Et₂ O), 81 mg (0.84 ml, 1.26 mmol) of n-butyllithium (1.5Msolution in hexanes), 86 mg (1.26 ml, 0.63 mmol) of zinc chloride (0.5Msolution in THF) and 10 mg (0.01 mmol) oftetrakis(triphenylphosphine)palladium (0).

PMR (CDCl₃): δ 1.36 (6H, s), 1.40 (3H, t, J=7.2 Hz), 2.37 (2H, d, J=4.9Hz), 4.38 (2H, q, J=7.2 Hz), 6.03 (1H, t, J=4.9 Hz), 7.01 (1H, d, J=8.0Hz), 7.27 (1H, dd, J=1.7, 8.0 Hz), 7.31-7.41 (5H, m), 7.53 (1H, d, J=1.7Hz), 7.59 (2H, d, J=8.2 Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl!benzoate(Compound 90)

Employing the same general procedure as for the preparation of ethyl4-((7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (pale yellow oil)using 429 mg (4.2 mmol) of phenylacetylene, 60 mg (0.08 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.32 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.38 (2H, d, J=5.0Hz), 4.38 (2H, q, J=7.1 Hz), 6.53 (1H, t, J=5.0 Hz), 7.32-7.38 (3H, m),7.43 (1H, dd, J=1.6, 7.9 Hz), 7.50 (1H, d, J=1.6 Hz), 7.54 (1H, d, J=1.6Hz), 7.56 (1H, d, J=4.8), 7.61 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=7.9Hz), 8.03 (2H, d, J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3-methyl)butynyl)naphth-2-ylethynyl!benzoate (Compound 91)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl)benzoate(Compound 87) was converted into the title compound (pale yellow solid)using 353 mg (4.2 mmol) of 2-methyl-3-butyn-2-ol, 60 mg (0.08 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.28 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.65 (6H, s), 2.31(2H, d, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 6.39 (1H, t, J=4.8 Hz), 7.38(1H, dd, J=1.6, 7.9 Hz), 7.46 (1H, d, J=1.6 Hz), 7.56 (1H, d, J=7.9 Hz),7.58 (2H, d, J=8.2 Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl 4- (7,8-dihydro-8,8-dimethyl-5-(1-propynyl)-naphth-2-ylethynyl!benzoate (Compound 92)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (pale yellow oil)using 168 mg (4.2 mmol) of propyne, 60 mg (0.08 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.28 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.08 (3H, s), 2.30(2H, d, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 6.33 (1H, t, J=4.8 Hz), 7.40(1H, dd, J=1.6, 7.9 Hz), 7.45 (1H, d, J=1.6 Hz), 7.59 (1H, d, J=7.9 Hz),7.61 (2H, d, J=8.2 Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)-naphth-2-yl)ethynyl!benzoate(Compound 93)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (pale yellow oil)using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.06 (3H, t, J=7.3 Hz), 1.28 (6H, s), 1.39 (3H, t, J=7.1Hz), 1.65 (2H, sext, J=7.3 Hz), 2.30 (2H, d, J=4.8 Hz), 2.41 (2H, t,J=7.3 Hz), 4.37 (2H, q, J=7.1 Hz), 6.34 (1H, t, J=4.8 Hz), 7.40 (1H, dd,J=1.6, 7.9 Hz), 7.45 (1H, d, J=1.6 Hz), 7.59 (2H, d, J=8.1 Hz), 7.62(1H, d, J=7.9 Hz), 8.01 (2H, d, J=8.1 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-2-yl)ethynyl!benzoate(Compound 94)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoate(Compound 75), 200 mg (0.42 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (pale yellow oil)using 70 mg (0.84 mmol) of 3,3-dimethyl-1-butyne, 60 mg (0.08 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) ofcuprous iodide.

PMR (CDCl₃): δ 1.28 (6H, s), 1.35 (9H, s), 1.40 (3H, t, J=7.1 Hz), 2.29(2H, d, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 6.32 (1H, t, J=4.8 Hz), 7.40(1H, dd, J=1.6, 7.9 Hz), 7.45 (1H, d, J=1.6 Hz), 7.59 (3H, d, J=8.1 Hz),8.01 (2H, d, J=8.1 Hz).

Ethyl 4- (7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl!benzoate(Compound 95)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71), 300 mg (0.63 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (colorless oil)using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithiumchloride and 41 mg (1.54 ml, 1.88 mmol) of methyllithium (1.22M solutionin Et₂ O).

PMR (CDCl₃): δ 1.27 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.05 (3H, d, J=1.9Hz), 2.21 (2H, dd, J=1.9, 4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 5.81 (1H, dt,J=1.9, 4.8 Hz), 7.21 (1H, d J=8.0 Hz), 7.38 (1H, dd, J=1.6, 8.0 Hz),7.47 (1H, d, J=1.6 Hz), 7.59 (2H, d, J=8.1 Hz), 8.02 (2H, d, J=8.1 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl!benzoate(Compound 96)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl!benzoate(Compound 71), 300 mg (0.63 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 87) was converted into the title compound (colorless oil)using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithiumchloride and 120 mg (1.1 ml, 1.88 mmol) of tert-butyllithium (1.7Msolution in pentane).

PMR (CDCl₃): δ 1.24 (6H, s), 1.35 (9H, s), 1.40 (3H, t, J=7.1 Hz), 2.15(2H, d, J=4.9 Hz), 4.38 (2H, q, J=7.1 Hz), 6.00 (1H, t, J=4.9 Hz), 7.34(1H, dd J=2.0, 8.1 Hz), 7.48 (1H, d, J=2.0 Hz), 7.59 (2H, d, J=8.2 Hz),7.63 (1H, d, J=8.1 Hz), 8.02 (2H, d, J=8.2 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97)

To a solution of 50 mg (0.13 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoate (Compound89) in 1 ml of argon saturated THF was added 27 mg (1.3 ml, 0.65 mmol)of argon saturated LiOH (0.5M aqueous solution). The reaction mixturewas stirred at room temperature for 24 hours under an atmosphere ofargon, concentrated in vacuo and the resulting residue partitionedbetween water and hexanes. The layers were separated and the aqueousfraction was acidified to pH 1 with 2N HCl. The product was extractedinto Et₂ O, dried over MgSO₄, and concentrated in vacuo to give thetitle compound as a pale yellow solid.

PMR (DMSO-d₆): δ 1.37 (6H, s), 2.38 (2H, d, J=4.7 Hz), 6.03 (1H, t,J=4.7 Hz), 6.99 (1H, d, J=8.1 Hz), 7.26 (1H, dd, J=1.7, 8.1 Hz),7.30-7.42 (5H, m), 7.52 (1H, d, J=1.7 Hz), 7.58 (2H, d, J=8.2 Hz), 8.00(2H, d, J=8.2 Hz).

4-(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)-naphth-2-yl)ethynyl!benzoicacid (Compound 98)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 22 mg (0.05 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl!benzoate(Compound 90) was converted to the title compound (pale yellow solid)using 11 mg (0.5 ml, 0.26 mmol) of LiOH (0.5M aqueous solution).

PMR (CDCl₃): δ 1.33 (6H, s), 2.40 (2H, d, J=4.9 Hz), 6.54 (1H, t, J=4.9Hz), 7.33-7.40 (3H,m), 7.45 (1H, dd, J=1.6, 7.9 Hz), 7.51 (1H, d, J=1.6Hz), 7.55 (1H, d, J=1.6 Hz), 7.57 (1H, d, J=4.8), 7.65 (2H, d, J=8.2Hz), 7.72 (1H, d, J=7.9 Hz), 8.12 (2H, d, J=8.2 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3-methyl)butynylnaphth-2-yl ethynyl!benzoic acid (Compound 99)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 79 mg (0.19 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3-methyl)butynyl)naphth-2-yl)ethynyl!benzoate(Compound 91) was converted to the title compound (pale yellow solid)using 40 mg (1.92 ml, 0.96 mmol) of LiOH (0.5M aqueous solution).

PMR (acetone-d₆): δ 1.29 (6H, s), 1.56 (6H, s), 2.35 (2H, d, J=5.1 Hz),6.39 (1H, t, J=5.1 Hz), 7.45 (1H, dd, J=1.6, 7.9 Hz), 7.46 (1H, d, J=1.6Hz), 7.64 (1H, d, J=7.9 Hz), 7.68 (2H, d, J=8.2 Hz), 8.06 (2H, d, J=8.2Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl!benzoicacid (Compound 100)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 75 mg (0.20 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl!benzoate(Compound 92) was converted to the title compound (pale yellow solid)using 42 mg (2 ml, 1.0 mmol) of LiOH (0.5M aqueous solution).

PMR (DMSO-d₆): δ 1.21 (6H, s), 2.05 (3H, s), 2.28 (2H, d, J=4.7 Hz),6.36 (1H, t, J=4.7 Hz), 7.46 (1H, dd, J=1.6, 7.9 Hz), 7.48 (1H, d, J=1.6Hz), 7.55 (1H, d, J=7.9 Hz), 7.66 (2H, d, J=8.2 Hz), 7.96 (2H, d, J=8.2Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethylbutynyl)naphth-2-yl)ethynyl!benzoic acid (Compound 101)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 52 mg (0.13 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-2-yl)ethynyl!benzoate(Compound 94) was converted to the title compound (pale yellow solid)using 26 mg (1.25 ml, 0.63 mmol) of LiOH (0.5M aqueous solution).

PMR (acetone-d₆): δ 1.29 (6H, s), 1.33 (9H, s), 2.34 (2H, d, J=4.8 Hz),6.33 (1H, t, J=4.8 Hz), 7.45 (1H, dd, J=1.6, 7.9 Hz), 7.52 (1H, d, J=1.6Hz), 7.64 (1H, d, J=8.1 Hz), 7.67 (2H, d, J=8.0 Hz), 8.06 (2H, d, J=8.0Hz).

4- (7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl!benzoic acid(Compound 102)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl)benzoic acid(Compound 97), 37 mg (0.11 mmol) of ethyl 4-(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl!benzoate (Compound 95)was converted to the title compound (white solid) using 23 mg (1.1 ml,0.54 mmol) of LiOH (0.5M aqueous solution).

PMR (DMSO-d₆): δ 1.21 (6H, s), 2.02 (3H, br s), 2.17 (2H, br s), 5.87(1H, br s), 7.26 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=8.2), 7.47 (1H, s),7.65 (2H, d, J=8.1 Hz), 7.67 (2H, d, J=8.1 Hz).

4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl!benzoicacid (Compound 103)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 51 mg (0.13 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl!benzoate(Compound 96) was converted to the title compound (white solid) using 28mg (1.3 ml, 0.66 mmol) of LiOH (0.5M aqueous solution).

PMR (acetone-d₆): δ 1.24 (6H, s), 1.35 (9H, s), 2.16 (2H, d, J=4.9 Hz),6.06 (1H, t, J=4.9 Hz), 7.40 (1H, dd, J=2.0, 8.1 Hz), 7.50 (1H, d, J=2.0Hz), 7.64 (2H, d, J=8.2 Hz), 7.71 (1H, d, J=8.1 Hz), 8.03 (2H, d, J=8.2Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl!benzoicacid (Compound 104)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl!benzoic acid(Compound 97), 177 mg (0.43 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl!benzoate(Compound 88) was converted to the title compound (white solid) using 91mg (4.3 ml, 2.14 mmol) of LiOH (0.5M aqueous solution).

PMR (acetone-d₆): δ 1.34 (6H, s), 2.45 (2H, d, J=4.9 Hz), 6.61 (1H, t,J=4.9 Hz), 7.42 (1H, dd, J=1.7, 8.1 Hz), 7.61 (2H, d, J=3.4 Hz), 7.67(2H, d, J=8.2 Hz), 7.87 (1H, d, J=8.1 Hz), 7.92 (1H, d, J=1.7 Hz), 8.02(2H, d, J=8.2 Hz).

Ethyl 4-(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl!benzoate(Compound 107)

To 500 mg (1.28 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl)benzoate(Compound 1) was added 0.21 ml (1.40 mmol) of cyanotrimethylsilane and 6drops of boron trifluride etherate. The resulting dark mixture washeated at 60° C. for 30 minutes, cooled to room temperature and purifiedby flash chromatography (silica, 25% EtOAc-hexane) to yield the titlecompound as a clear oil.

PMR (CDCl₃): δ 0.25 (9H, s), 1.34 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.90(2H, m), 2.25 (1H, m), 2.35 (1H, m), 4.39 (2H, q, J=7.1 Hz), 7.44 (1H,dd, J=1.6, 8.4 Hz), 7.51 (1H, s), 7.61 (2H, d, J=8.4 Hz), 7.64 (1H, d,J=8.4 Hz), 8.04 (2H, d, J=8.3 Hz).

Ethyl 4- (5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 108)

To 215 mg (0.48 mmol) of ethyl 4-(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-tri-methylsiloxynaphth-2-yl)ethynyl!benzoate(Compound 107) was added 0.5 ml of pyridine and 3 drops of phosphorousoxychloride. The resulting dark mixture was gently refluxed at 115° C.for 30 minutes, cooled to room temperature and poured into crushed ice.The mixture was extracted with Et₂ O and the combined organic layerswere washed with water, dilute HCl and water. The organic phase wasconcentrated in vacuo to a gummy residue which was purified by flashchromatography (silica, 20% EtOAc-hexane) to as the title compound as apale yellow solid.

PMR (CDCl₃): δ 1.31 (6H, s), 1.41 (3H, t, J=7.2 Hz), 2.44 (2H, d, J=4.8Hz), 4.39 (2H, q, J=7.2 Hz), 6.89 (1H, t, J=4.8 Hz), 7.49 (3H, m), 7.60(2H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz).

Ethyl 4-(5-carboxamido-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 109)

To a solution of 50 mg (0.14 mmol) of ethyl 4-(5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate (Compound108) in 1 ml of ethanol was added 1 ml of H₂ SO₄ (1M aqueous solution).This reaction mixture was heated at 80° C. overnight, 2 ml of water wasadded and the solution was extracted with EtOAc (3×2 ml). The combinedorganic layers were washed with sat. aqueous NaHCO₃ and brine, driedover MgSO₄, concentrated in vacuo and the residue purified by columnchromatography (silica, 20% EtOAc-hexane) to yield the title compound asa colorless oil.

PMR (CDCl₃): δ 1.31 (6H, s), 1.38 (3H, t, J=7.2 Hz), 2.46 (2H, d, J=4.8Hz), 4.33-4.38 (4H, m), 6.98 (1H, t, J=4.8 Hz), 7.35 (2H, d, J=8.2 Hz),7.56-7.59 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=8.0 Hz), 7.97 (1H, s), 8.02(2H, d, J=8.2 Hz).

Ethyl 4- (7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate (Compound110)

To a solution of 0.13 g (0.38 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 9) in 15 ml of dry benzene was added 0.67 g (2.90 mmol) of(methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent).The resulting mixture was heated at 50° C. for 30 minutes, cooled toroom temperature, partitioned between water (10 ml) and EtOAc (20 ml)and the layers separated. The organic layer was dried over Na₂ SO₄,concentrated in vacuo and purified by flash chromatography (silica, 10%EtOAc-hexane) to yield the title compound as a clear oil.

PMR (CDCl₃): δ 1.28 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.25 (2H, dd,J=1.8, 2.6 Hz), 4.37 (2H, q, J=7.1 Hz), 5.99 (1H, q, J=4.8 Hz), 6.45(1H, d, J=9.7 Hz), 7.00 (1H, d, J=7.8 Hz), 7.32 (1H, dd, J=1.6 6.2 Hz),7.46 (1H, s), 7.57 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.5 Hz).

Ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 113)

To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc(activated prior to use by washing with 2% HCl, water, 95% ethanol,acetone, anhydrous Et₂ O and then dried in vacuum for several hours) in20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol)of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxedfor 2 hours, cooled to room temperature and the precipitate filteredthrough Celite. The filtrate was washed with cold 15% H₂ SO₄, sat.aqueous NaHCO₃ and brine. The organic phase was dried over Na₂ SO₄ andconcentrated in vacuo to a yellow oil. Purification by flashchromatography (silica, 10% EtOAc-hexane) yielded the title compound asa light yellow solid.

PMR (CDCl₃): δ 1.30 (6H, s), 1.42 (3H, t, J=7.1 Hz), 1.75 (2H, m), 2.08(2H, m), 2.77 (2H, s), 4.22 (3H, m), 4.39 (2H, q, J=7.1 Hz), 7.38 (1H,dd, J=1.7, 6.5 Hz), 7.49 (1H, d, J=1.6 Hz), 7.59 (3H, m), 8.02 (2H, d,J=8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 114) and Ethyl 4-(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 115)

To a solution of 0.50 g (1.15 mmol) of ethyl 4-(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 113) in 25 ml of dry benzene was added 2.12 g (8.90 mmol) of(methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent).The reaction mixture was heated at 50° C. for 30 minutes, cooled to roomtemperature and concentrated in vacuo. The residue was diluted withEtOAc, washed with water and brine, dried over Na₂ SO₄ and concentratedin vacuo to an oil. Purification by flash chromatography (silica, 25%EtOAc-hexane) yielded the title compounds as solids in a ratio of 5 to1, respectively.

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 114):

PMR (CDCl₃): δ 1.17 (3H, t, J=2.8 Hz), 1.30 (6H, s), 1.41 (3H, t, J=7.1Hz), 2.26 (2H, d, J=4.6 Hz), 3.46 (2H, s), 4.12 (2H, q, J=7.2 Hz), 4.38(2H, q, J=7.1 Hz), 5.96 (1H, s), 7.17 (1H, d, J=8.0 Hz), 7.36 (1H, dd,J=1.7, 6.4 Hz), 7.48 (1H, d, J=1.7 Hz), 7.58 (2H, d, J=6.5 Hz), 8.01(2H, d, J=6.5 Hz).

Ethyl 4-(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-ylethynyl!benzoate(Compound 115)

PMR (CDCl₃): δ 1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.73 (3H, t, J=6.7Hz), 3.22 (2H, m), 4.22 (2H, q, J=7.1 Hz), 4.39 (2H, q, J=7.1 Hz), 6.30(1H, d, J=1.8 Hz), 7.35 (1H, dd, J 1.7, 6.6 Hz), 7.55 (1H, d, J=1.6 Hz),7.60 (3H, dd, J=2.0, 6.4 Hz), 8.04 (2H, d, J=6.5 Hz).

Trimethylsilylethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 116)

To a solution of 0.24 g (0.73 mmol) of 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoic acid(Compound 7) in 10 ml of dry CH₂ Cl₂ was added 0.09 g (0.74 mmol) ofdimethylaminopyridine, 0.115 ml (0.80 mmol) of trimethylsilylethanol and0.17 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride. The reaction mixture was stirred at 25° C. for 5 hours,washed with sat. aqueous NaHCO₃ and brine, dried over Na₂ SO₄ andconcentrated in vacuo to an oil. Purification by flash chromatography(silica, 10% EtOAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ 0.09 (9H, s), 1.14 (2H, m), 1.42 (6H, s), 2.03 (2H, t,J=7.1 Hz), 2.74 (2H, t, J=6.5 Hz), 4.43 (2H, t, J=8.5 Hz), 7.45 (1H, dd,J=1.5, 6.7 Hz), 7.61 (3H, d, J=7.0 Hz), 8.03 (3H, t, J=6.7 Hz).

Trimethylsilylethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 117)

Employing the same general procedure as for the preparation of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 113), 0.38 g (0.89 mmol) of trimethylsilylethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoate(Compound 116), was converted into the title compound (yellow solid)using 0.50 g (7.65 mmol) of zinc, 0.20 ml (1.78 mmol) of ethylbromoacetate and 20 ml of dry benzene.

PMR (CDCl₃): δ 0.09 (9H, s), 1.14 (2H, m), 1.28 (8H, m), 1.74 (2H, m),2.07 (2H, m), 2.77 (2H, s), 4.20 (3H, m), 4.42 (3H, t, J=8.4 Hz), 7.37(1H, dd, J=1.6, 6.7 Hz), 7.49 (1H, s), 7.58 (3H, dd, J=3.8, 7.0 Hz),8.01 (2H, d, J=8.4 Hz).

4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoicacid (Compound 118)

To a solution of 0.25 g (0.49 mmol) of trimethylsilylethyl4-((5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxy-methylnaphth-2-yl)ethynyl!benzoate(Compound 117) in 5 ml of dry THF (flushed with argon) was added 1.48 ml(1.5 mmol) of tetrabutylammonium fluoride (1M solution in THF). Thereaction mixture was stirred at room temperature for 12 hours,concentrated in vacuo to an oil and slowly diluted with water. Thesolution was acidified to pH 4 with 10% HCl and extracted with Et₂ O.The organic layer was dried over Na₂ SO₄, concentrated in vacuo to anoil and purified by flash chromatography (silica, 90% EtOAc-hexane) togive the title compound as a white solid.

PMR (CDCl₃): δ 1.30 (9H, m), 1.72 (2H, m), 2.08 (2H, m), 2.78 (2H, s),4.21 (2H, q, J=7.0 Hz), 7.38 (1H, dd, J=1.5, 6.6 Hz), 7.50 (1H, s), 7.58(1H, d, J=8.2 Hz), 7.62 (2H, d, J=8.4 Hz), 8.10 (2H, d, J=8.4 Hz).

Ethyl 4-(5-hydroxy-8,8-dimethyl-5-carboethoxymethyl-5,6,7,8-tetrahydronaphth-3-yl)ethynyl!benzoate(Compound 119)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 113), 1.00 g (2.88 mmol) of ethyl 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoate(Compound 2) was converted into the title compound (light yellow solid)using 1.00 g (15.30 mmol) of zinc, 0.639 ml (5.76 mmol) of ethylbromoacetate and 70 ml of dry benzene.

PMR (CDCl₃): δ 1.30 (9H, m), 1.40 (3H, t, J=7.1 Hz), 1.75 (2H, m), 2.04(2H, m), 2.80 (2H, d, J=3.1 Hz), 4.21 (2H, m), 4.38 (2H, q, J=7.2 Hz),7.30 (1H, d, J=8.3 Hz), 7.41 (1H, dd, J=1.8, 6.4 Hz), 7.57 (2H, d, J=6.7Hz), 7.81 (1H, d, J=1.8 Hz), 8.03 (2H, d, J=8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl!benzoate(Compound 120) and Ethyl 4-(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 121)

Employing the same general procedure as for the preparations of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl!benzoate(Compound 114) and ethyl 4-(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoate(Compound 115), 0.57 g (1.31 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl!benzoate(Compound 119) was converted into the title compounds (yellow solid andwhite solid, respectively) using 15 ml of dry benzene, 6 ml of dry THFand 2.42 g (10.1 mmol) of (methoxycarbonylsulfamoyl) triethylammoniumhydroxide (Burgess Reagent).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl!benzoate(Compound 120)

PMR (CDCl₃): δ 1.22 (3H, t, J=7.1 Hz), 1.29 (6H, s), 2.70 (2H, d, J=4.4Hz), 3.49 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.00 (2H, q, J=7.1 Hz), 5.96(1H, t, J=4.5 Hz), 7.35 (3H, m), 7.58 (2H, d, J=8.4 Hz), 8.02 (2H, d,J=7.9 Hz).

Ethyl 4-(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 121)

PMR (CDCl₃): δ 1.31 (9H, m), 1.74 (2H, q, J=6.7 Hz), 3.24 (2H, t, J=3.3Hz), 4.22 (2H, q, J=7.1 Hz), 4.40 (2H, q, J=7.1 Hz), 6.33 (1H, s), 7.37(1H, d, J=7.9 Hz), 7.50 (1H, d, J=8.3 Hz), 7.59 (2H, d, J=7.7 Hz), 7.79(1H, s), 8.04 (2H, d, J=8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl!benzoate(Compound 122)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (colorless solid)using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) oftetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared bythe addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5Msolution in hexane) to a cold solution (-78° C.) of 53.4 mg (0.784 mmol)of furan in 1.0 mL of THF).

PMR (CDCl₃): δ 1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 2.35 (2H, d, J=5.0Hz), 4.39 (2H, q, J=7.1 Hz), 6.41 (1H, t, J=5.0 Hz), 6.50 (2H, s), 7.36(1H, d, J=8.0 Hz), 7.45 (1H, dd, J=1.7, 8.0 Hz), 7.49 (1H, s), 7.57 (2H,d, J=8.2 Hz), 7.63 (1H, d, J=1.7 Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl!benzoate(Compound 123)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 328.0 mg (0.685 mmol) of ethyl 4-(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (colorless solid)using 186.8 mg (1.37 mmol) of zinc chloride 37.1 mg (0.03 mmol) oftetrakis(triphenylphosphine)palladium(0) and 2-lithiothiophene (preparedby the addition of 65.9 mg (0.69 ml, 1.03 mmol) of n-butyllithium (1.5Msolution in hexane) to a cold solution (-78° C.) of 86.5 mg (1.03 mmol)of thiophene in 1.0 mL of THF).

PMR (CDCl₃): δ 1.33 (6H, s), 1.36 (3H, t, J=7.1 Hz), 2.38 (2H, d, J=4.7Hz), 4.34 (2H, q, J=7.2 Hz), 6.25 (1H, t, J=4.7 Hz), 7.13 (2H, m), 7.47(4H, m), 7.62 (2H, d, J=8.5 Hz), 8.00 (2H, d, J=8.5 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl!benzoic acid(Compound 124)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl!benzoic acid(Compound 84), 60.3 mg (0.15 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl!benzoate(Compound 122) was converted into the title compound (colorless solid)using 16.0 mg (0.38 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.26 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.41 (1H, t,J=4.9 Hz), 6.60 (2H, m), 7.45-7.53 (3H, m), 7.64 (2H, d, J=8.3 Hz), 7.75(1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.3 Hz).

4- (7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl!benzoicacid (Compound 125)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-2-yl)ethynyl!benzoic acid(Compound 84), 70.0 mg (0.17 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl!benzoate(Compound 123) was converted into the title compound (colorless solid)using 17.8 mg (0.42 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.27 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.23 (1H, t,J=4.9 Hz), 7.14 (2H, m), 7.38-7.56 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.92(2H, d, J=8.3 Hz).

4- (5-cyano-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoic acid(Compound 129)

To 76 mg (0.24 mmol) of 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl!benzoic acid(Compound 8) was added 0.06 ml (0.48 mmol) of cyanotrimethylsilane and 6drops of boron trifluoride etherate. The resulting dark mixture washeated at 80° C. for 45 minutes, cooled to room temperature and purifiedby flash chromatography (silica, 50% EtOAc-hexane) to yield the titlecompound as a yellow solid.

PMR (CDCl₃): δ 1.31 (6H, s), 2.45 (2H, d, J=4.8 Hz), 6.91 (1H, t, J=4.8Hz), 7.36 (1H, d, J=8.0 Hz), 7.51 (1H, dd, J=1.8, 8.0 Hz), 7.65 (2H, d,J=8.4 Hz), 7.69 (1H, s), 8.10 (2H, d, J=8.4 Hz).

4- (5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl!benzoic acid(Compound 130)

Employing the same general procedure as for the preparation of 4-(8-cyano-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoic acid(Compound 129), 63 mg (0.26 mmol) of 4-(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl!benzoic acid(Compound 7) was converted into the title compound (yellow powder) using0.06 ml (0.54 mmol) of cyanotrimethylsilane and 6 drops of borontrifluoride etherate.

PMR (CDCl₃): δ 1.32 (6H, s), 2.45 (2H, d, J=4.8 Hz), 6.90 (1H, t, J=4.8Hz), 7.49 (3H, m), 7.65 (2H, d, J=8.4 Hz), 8.10 (2H, d, J=8.4 Hz).

Ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-3-yl)ethynyl!benzoate(Compound 163)

Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoate(Compound 67), 200.0 mg (0.42 mmol) of ethyl 4-(5-triflouromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl!benzoate(Compound 66) was converted into the title compound (colorless solid)using 113.8 mg (0.835 mmol) of zinc chloride and 4-methylphenyllithium(prepared by adding 40.4 mg (0.42 ml, 0.63 mmol) of n-butyllithium (1.5Msolution in hexane) to a cold solution (-78° C.) of 108.0 mg (0.63 mmol)of 4-bromotoluene in 1.0 ml of THF).

PMR (CDCl₃): δ 1.36 (6H, s), 1.41 (3H, t, J=7.2 Hz), 2.36 (2H, d, J=4.7Hz), 2.43 (3H, s), 4.39 (2H, q, J=7.2 Hz), 6.01 (1H, t, J=4.7 Hz), 7.26(4H, m), 7.40 (2H, m ), 7.53 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.4 Hz).

4-(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-2-yl)ethynyl!benzoicacid (Compound 164)

Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl!benzoicacid (Compound 78), 26.0 mg (0.06 mmol) of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-3-yl)ethynyl!benzoate(Compound 163) was converted into the title compound (colorless solid)using 6.5 mg (0.16 mmol) of LiOH in H₂ O.

PMR (d₆ -DMSO): δ 1.28 (6H, s), 2.31 (2H, d, J=4.7 Hz), 2.33 (3H, s)5.98 (1H, t, J=4.5 Hz), 7.00 (1H, s), 7.20 (4H, m), 7.44 (2H, m), 7.58(2H, d, J=8.5 Hz), 7.90 (2H, d, J=8.3 Hz).

What is claimed is:
 1. A compound of the formula ##STR10## wherein R₁ ishydrogen or alkyl of 1 to 10 carbons; R₂ and R₃ are hydrogen, or alkylof 1 to 6 carbons and the substituted ethynyl group occupies either the2 or the 3 position of the dihydronaphthalene nucleus;m is an integerhaving the value of 0-3; o is an integer having the value 0-3; Y is aphenyl group, or heteroaryl selected from a group consisting of pyridyl,thienyl, furyl, and thiazolyl, said groups being optionally substitutedwith one or two R₂ groups; A is (CH₂)_(n) where n is 0-5, lower branchedchain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenylhaving 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbonsand 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, ortri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, and R₂₂is a 5 or 6 membered heteroaryl group optionally substituted with a C₁to C₁₀ alkyl group and having 1 to 3 heteroatoms, said heteroatoms beingselected from a group consisting of O, S, and N.
 2. A compound of claim1 where Y is phenyl, pyridyl, thienyl or furyl.
 3. A compound of claim 1where Y is thienyl or furyl.
 4. A compound of claim 1 where R₂ ishydrogen.
 5. A compound of claim 1 where R₃ is hydrogen.
 6. A compoundof claim 1 where R₂₂ is a 5 or 6 membered heteroaryl group having 1 or 2heteroatoms.
 7. A compound of claim 6 where R₂₂ is 2-thiazolyl, 2-furyl,2-thienyl or 2-pyridyl.
 8. A compound of the formula ##STR11## whereinR₁ is hydrogen or alkyl of 1 to 10 carbons; R₂ and R₃ are hydrogen, oralkyl of 1 to 6 carbons and the substituted ethynyl group occupieseither the 2 or the 3 position of the dihydronaphthalene nucleus;m is aninteger having the value of 0-3; o is an integer having the value 0-3; Yis phenyl or pyridyl, said groups being optionally substituted with oneor two R₂ groups; A is (CH₂)_(n) where n is 0-5, lower branched chainalkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptablesalt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO,CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-loweralkylsilyl, where R₇ is an alkyl, cydloalkyl or alkenyl group containing1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, and R₂₂is a 5 or 6 membered heteroaryl group having 1 to 2 heteroatoms, saidheteroatoms being selected from a group consisting of O, S, and N.
 9. Acompound of claim 8 where A is (CH₂)_(n) where n is 0-5 and where B isCOOH or a pharmaceutically acceptable salt thereof, COOR₈, or CONR₉ R₁₀.10. A compound of claim 9 where n is 0 and B is COOH or apharmaceutically acceptable salt thereof.
 11. A compound of the formula##STR12## wherein R₈ is hydrogen, an alkyl group of 1 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, andR₂₂ isa 5 or 6 membered heteroaryl group having 1 to 2 heteroatoms, saidheteroatoms being selected from a group consisting of O, S, and N, andthe substituted ethynyl group occupies the 2 or 3 position of thedihydronaphthalene nucleus.
 12. A compound of claim 11 where R₂₂ is2-thiazolyl.
 13. A compound of claim 12 where R₈ is H or C₂ H₅.
 14. Acompound of claim 11 where R₂₂ is 2-pyridyl.
 15. A compound of claim 14where R₈ is H or C₂ H₅.
 16. A compound of claim 11 where R₂₂ is 2-furyl.17. A compound of claim 16 where R₈ is H or C₂ H₅.
 18. A compound ofclaim 11 where R₂₂ is 2-thienyl.
 19. A compound of claim 18 where R₈ isH or C₂ H₅.
 20. A compound of claim 1 where Y is phenyl.
 21. A compoundof claim 20 where the phenyl ring is 1,4 (para) substituted.
 22. Acompound of claim 1 where Y is pyridyl.
 23. A compound of claim 22 wherethe pyridyl ring is substituted in the 2 and 5 positions.